Fused pyrrolecarboxamides; GABA brain receptor ligands

Abstract

Substituted pyrrolecarboxamide compounds are disclosed. These compounds are highly selective agonists, antagonists or inverse agonists for GABA_A brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABA_A brain receptors and are therefore useful in the diagnosis and treatment of anxiety, depression, Alzheimer's dementia, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory. Pharmaceutical compositions, including packaged pharmaceutical compositions, are further provided. compounds of the invention are also useful as probes for the localization of GABA_A receptors in tissue samples.

Description

This application is a continuation-in-part of U.S. Ser. No. 09/387,311, filed Aug. 31, 1999, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to fused pyrrolecarboxamides. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of certain central nervous system (CNS) diseases. This invention also relates to the use of these fused pyrrolecarboxamide compounds in combination with one or more other CNS agents to potentiate the effects of the other CNS agents. Additionally this invention relates to the use such compounds as probes for the localization of GABA_A receptors in tissue sections.

2. Description of the Related Art

The GABA_A receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, γ-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABA_A receptor, which causes alteration in chloride conductance and membrane polarization.

A number of cDNAs for GABA_A receptor subunits have been characterized. To date at least 6α, 3β, 3γ, 1ε, 1δ and 2ρ subunits have been identified. It is generally accepted that native GABA_A receptors are typically composed of 2α, 2β, and 1γ subunits (Pritchett & Seeburg Science 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998; 6:1-18). Evidence such as message distribution, genome localization and biochemical study results suggest that the major naturally occurring receptor combinations are α₁β₂γ₂, α₂β₃γ₂, α₃β₃γ₂, and α₅β₃γ₂ (Mohler et. al. Neuroch. Res. 1995; 20(5): 631-636).

Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABA_A receptor. In addition to the benzodiazepine site, the GABA_A receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the barbiturate site. The benzodiazepine site of the GABA_A receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6^th ed., 1991, pp. 145-148, Oxford University Press, New York). Early electrophysiological studies indicated that a major action of the benzodiazepines was enhancement of GABAergic inhibition. Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABA_A receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABA_A receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists.

The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early and the distribution of activities at different receptor subtypes has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have a long history of pharmaceutical use as anxiolytics, these compounds often exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.

GABA_A selective ligands may also act to potentiate the effects of certain other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when used in combination with GABA_A selective ligands than when used alone.

Various compounds have been prepared as benzodiazepine agonists and antagonists. For Example, U.S. Pat. Nos. 3,455,943, 4,435,403, 4,596,808, 4,623,649, and 4,719,210, German Patent No. DE 3,246,932, and Liebigs Ann. Chem. 1986, 1749 teach assorted benzodiazepine agonists and antagonists and related anti-depressant and central nervous system active compounds.

U.S. Pat. No. 3,455,943 disclosed indole derivatives.

Other references, such as U.S. Pat. No. 4,435,403 and German patent DE 3,246,932 disclose pyrimidino[5,4-b]indoles and beta-carboline derivatives.

A variety of indole-3-carboxamides is described in the literature. See, for example, J. Org. Chem., 42: 1883-1885 (1977); J. Heterocylic Chem., 14: 519-520 (1977). Also, U.S. Pat. Nos. 5,804,686 and 6,080,873 and PCT International Publication WO 97/26243, all of which are assigned to Neurogen Corporation, disclose fused pyrrolecarboxamides.

SUMMARY OF THE INVENTION

In a preferred aspect, this invention provides pyrrolecarboxamides that bind with high affinity and high selectivity to the benzodiazepine site of the GABA_A receptor, including human GABA_A receptors.

Thus, the invention provides compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula I.

The invention further comprises methods of treating patients suffering from CNS disorders with an effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pet) or livestock animals suffering from CNS disorders with an effective amount of a compound of the invention is encompassed by the invention.

In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound.

Additionally this invention relates to the use of the compounds of the invention as probes for the localization of GABA_A receptors in tissue sections.

Accordingly, a broad aspect of the invention is directed to compounds of the formula ##STR00001##
or the pharmaceutically acceptable salts thereof wherein:

• T is halogen, hydrogen, hydroxyl, amino, alkyl or alkoxy;
• X is hydrogen, hydroxy, amino, benzyl, t-butoxycarbonyl, benzyloxycarbonyl, alkyl, or alkoxy;
• G represents ##STR00002##
•  where
  • Q is an optionally substituted aryl or optionally substituted heteroaryl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;
  • W is chosen from hydrogen, —O—, —NH—, —NR₇—, —S(O)_0-2—, —C(═O)—, —OC(═O)—, —C(═O)O—, —C(═O)NH—, —NHC(═O)—, —NR₇C(═O)—, —NHS(O)_0-2—, —NR₇S(O)_0-2—, —S(O)_0-2NH—, —S(O)_0-2NR₇—, and CR₇R₈ where R₇ and R₈ are the same or different and represent hydrogen, alkyl, or CR₇R₈ represents a cyclic moiety having 3-7 carbon atoms, wherein W may not be hydrogen when Q is phenyl, 2- or 3-thienyl, or 2-, 3-, or 4 pyridyl, indolyl, imidazolyl, or pyridazinyl;
  • Z is hydrogen, hydroxy, cycloalkyl(alkoxy), amino, mono- or di(alkyl₁)amino, azacycloalkyl, —O(alkyl₁), —S(O)_0-2(alkyl₁), —C(═O)(alkyl₁), —OC(═O)(alkyl₁), —OC(═O)H, —C(═O)O(alkyl₁), —C(═O)OH, —C(═O)NH(alkyl₁), —C(═O)N(alkyl₁)₂, —C(═O)NH₂, —NHC(═O)(alkyl₁), —NHC(═O)H, —N(alkyl₁)C(═O)(alkyl₁), —NHS(O)_0-2(alkyl₁), —N(alkyl₁)S(O)_0-2(alkyl₁), —S(O)_0-2NH(alkyl₁), —S(O)_0-2(alkyl₁)N(alkyl₁),
    • wherein each alkyl₁ is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds or combinations thereof, and is unsubstituted or substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy, or
  • Z is —N(R_N)₂S(O)_0-2(R_S) where
    • each R_N is independently hydrogen or alkyl where the alkyl is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy,
    • R_S is hydroxy, alkoxy, heteroaryl, aryl, or alkyl where
      • each aryl and heteroaryl is optionally substituted with one or two of alkyl, hydroxy, alkoxy, trifluoromethyl, halogen, amino, or mono- or dialkylamino; and
      • each alkyl is optionally substituted with hydroxy, alkoxy, trifluoromethyl, halogen, amino, mono- or di-alkylamino, aryl, or heteroaryl; or
  • Z is phenyl or phenylalkyl where the phenyl portion is optionally substituted with alkyl, hydroxy, alkoxy, trifluoromethyl, halogen, amino, or mono- or dialkylamino, or
  • Z is 2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or 3-pyrrolyl, azeditinyl, norborn-2-yl, or adamantan-2-yl; each of which may be substituted on a tertiary carbon or a secondary nitrogen with C₁-C₆alkyl, or
  • Z is NR₉COR₁₀ where R₉ and R₁₀ are the same or different and represent hydrogen or alkyl or cycloalkyl, or
  • Z is connected, optionally through W, to Q to form a 1-6 membered ring; or
  • Z represents a group of the formula: ##STR00003##
  •  where
    • p is 1, 2, or 3;
    • D and D′ independently represent oxygen, NR_y or CHR_y provided that only one of D and D′ may be NR_y, and only one of D and D′ may be oxygen, where each R_y is hydrogen or alkyl; and
    • R_z is hydrogen or alkyl, or
  • Z represents a group of the formula: ##STR00004##
  •  where
    • p is 1, 2, or 3;
    • q is 0, 1, or 2;
    • each R_z is independently hydrogen or alkyl; or
  • Z represents a group of the formula: ##STR00005##
  •  where
    • s is 0, 1, 2 or 3, and the sum of s and m is not less than 1;
    • R_o is hydroxy, C₁-C₆alkoxy, amino, mono- or dialkylamino where each alkyl is independently optionally substituted with amino, or mono- or dialkylamino, or
    • R_o is a group of the formula ##STR00006##
    •  where p, D, D′, and R_z are as defined above; ##STR00007##
    •  independently represent a carbon chain optionally substituted with halogen, oxo, cyano, nitro, amino, mono or dialkylamino, alkyl, alkenyl, alkynyl, trifluoromethyl, trifluoromethoxy, or cycloalkyl;
    • wherein
      • k is 0, 1, 2, or 3;
      • m is 0, 1, 2, or 3; and ##STR00008##
      •  represents a carbon chain optionally substituted with R₅ and R₆ and n is 0, 1, 2, or 3; and
• R₃, R₄, R₅, and R₆ are the same or different and are independently selected at each occurrence from hydrogen, alkyl, —COR₁₁ or —CO₂R₁₁ where R₁₁ is alkyl or cycloalkyl having 3-7 carbon atoms; or —CONR₁₂R₁₃ where R₁₂ and R₁₃ are selected independently from hydrogen, alkyl, cycloalkyl having 3-7 carbon atoms, phenyl, 2-, 3-, or 4-pyridyl, or NR₁₂R₁₃ forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or
• R₃ and R₄ together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms; or
• R₅ and R₆ together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms;
  • where each alkyl group forming an R₃, R₄, R₅, or R₆ substituent or portion thereof may be substituted independently with hydroxy or mono- or dialkylamino where each alkyl is independently alkyl or cycloalkyl.

In another aspect, the invention provides intermediates useful for preparing compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In addition to compounds of Formula I described above, the invention also encompasses compounds of the same general formula and the pharmaceutically acceptable salts thereof, wherein:

• T is halogen, hydrogen, hydroxyl, C₁-C₆ amino, alkyl or C₁-C₆ alkoxy;
• X is hydrogen, hydroxy, amino, C₁-C₆ alkyl, or C₁-C₆ alkoxy;
• G represents ##STR00009##
•  where
  • Q is phenyl, 2- or 3-thienyl, or 2-, 3-, or 4 pyridyl, 2-, 4-, or 5-pyrimidinyl, indolyl, imidazolyl, pyridazinyl, 1,4-benzodioxazinyl, 1,3-benzodioxolyl or imidazo[1,2-a]pyridinyl, all of which may be substituted by one or more of hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, nitro, amino, and mono- or dialkyl(C₁-C₆)amino;
  • W is chosen from hydrogen, —O—, —NH—, —NR₇—, —S(O)_0-2—, —C(═O)—, —OC(═O)—, —C(═O)O—, —C(═O)NH—, —NHC(═O)—, —NR₇C(═O)—, —NHS(O)_0-2—, —NR₇S(O)_0-2—, —S(O)_0-2NH—, —S(O)_0-2R₇H—, and CR₇R₈ where R₇ and R₈ are the same or different and represent hydrogen, alkyl, or R₇-R₈ taken together represents a cyclic moiety having 3-7 carbon atoms, wherein W may not be hydrogen when Q is phenyl, 2- or 3-thienyl, or 2-, 3-, or 4 pyridyl, indolyl, imidazolyl, or pyridazinyl;
  • Z is hydrogen, hydroxy, C₃-C₇ cycloalkyl(C₁-C₆ alkoxy), amino, mono- or di(C₁-C₆ alkyl₁)amino, or C₃-C₇ azacycloalkyl, —O(C₁-C₆ alkyl₁), —S(O)_0-2(C₁-C₆ alkyl₁), —C(═O) (C₁-C₆ alkyl₁), —OC(═O)(C₁-C₆ alkyl₁), —OC(═O)H, —C(═O)O(C₁-C₆ alkyl₁), —C(═O)OH, —C(═O)NH(C₁-C₆ alkyl₁), —C(═O)NH₂, —NHC(═O) (C₁-C₆ alkyl₁), —NHC(═O)H, —N(C₁-C₆ alkyl₁)C(═O) (C₁-C₆ alkyl₁), —NHS(O)_0-2(C₁-C₆ alkyl₁), —N(C₁-C₆ alkyl₁)S(O)_0-2(C₁-C₆ alkyl₁), —S(O)_0-2NH(C₁-C₆ alkyl₁), or —S(O)_0-2(C₁-C₆ alkyl₁)N(C₁-C₆alkyl₁),
    • wherein C₁-C₆ alkyl₁ is independently chosen at each occurrence and is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy, or
  • Z is —N(R_N)₂S(O)_0-2(R_S) where
    • each R_N is independently hydrogen or alkyl where the alkyl is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy,
    • R_S is hydroxy, alkoxy, or alkyl where the alkyl is optionally substituted with hydroxy, alkoxy, trifluoromethyl, halogen, amino, mono- or dialkylamino, aryl or heteroaryl,
  • Z is phenyl or phenyl(C₁-C₆)alkyl where the phenyl portion is optionally substituted with C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy, halogen, amino, or mono- or diC₁-C₆ alkylamino, or
  • Z is 2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or 3-pyrrolyl, or adamantane-2-yl; each of which may be substituted on a tertiary carbon or a secondary nitrogen with C₁-C₆alkyl, or
  • Z is NR₉COR₁₀ where R₉ and R₁₀ are the same or different and represent hydrogen or C₁-C₆ alkyl or C₃-C₇ cycloalkyl, or
  • Z is connected, optionally through W, to Q to from a 1-6 membered ring; or
  • Z represents a group of the formula: ##STR00010##
  •  where
    • p is 1, 2, or 3;
    • D and D′ independently represent oxygen, NR_y or CHR_y provided that only one of D and D′ may be NR_y where each R_y is hydrogen or C₁-C₆ alkyl; or and R_z is hydrogen or C₁-C₆ alkyl, or
  • Z represents a group of the formula: ##STR00011##
  •  where
    • p is 1, 2, or 3;
    • q is 0, 1, or 2;
    • R_z is hydrogen or C₁-C₆ alkyl; or
  • a group of the formula: ##STR00012##
  •  where
    • s is 0, 1, 2 or 3, and the sum of s and m is not less than 1;
    • R_o is hydroxy, C₁-C₆alkoxy, amino, mono- or diC₁-C₆alkylamino where each alkyl is independently optionally substituted with amino, mono- or diC₁-C₆alkylamino, or
    • R_o is a group of the formula ##STR00013##
    •  where p, D, D′, and R_z are as defined above; ##STR00014##
    •  independently represent a carbon chain optionally substituted with hydrogen, halogen, oxo, cyano, nitro, amino, mono or di(C₁-C₆)alkylamino, straight or branched chain C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, trifluoromethyl, trifluoromethoxy, or cycloC₁-C₆ alkyl;
    • wherein
      • k is 0, 1, 2, or 3;
      • m is 0, 1, 2, or 3; and ##STR00015##
      •  represents a carbon chain optionally substituted with R₅ and R₆ and n is 0, 1, 2, or 3;
• R₃, R₄, R₅, and R₆ are the same or different and are independently selected at each occurrence from hydrogen, C₁-C₆ alkyl, —COR₁₁ or —CO₂R₁₁ where R₁₁ is C₁-C₆alkyl or C₃-C₇ cycloalkyl; or
  • —CONR₁₂R₁₃ where R₁₂ and R₁₃ are selected independently from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, phenyl, 2-, 3-, or 4-pyridyl, or NR₁₂R₁₃ forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or
• R₃ and R₄ together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms; or
• R₅ and R₆ together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms; and
  where each alkyl group forming an R₃, R₄, R₅, or R₆ substituent or portion thereof may be substituted independently with hydroxy or mono- or dialkylamino where each alkyl is independently C₃-C₇ alkyl or cycloalkyl having 3-7 carbon atoms.

Such compounds will be referred to as compounds of Formula Ia. Particular compounds of the invention also include compounds of Formula I where Q is phenyl or pyridyl (compounds of Formula Ib) and compounds of Formula I where Q is phenyl or pyridyl; and either the group ##STR00016##
is substituted by oxo (compounds of Formula Ic).

When W is hydrogen, m is 0 and Z is absent resulting in Q groups that are optionally substituted with alkyl where the alkyl is optionally substituted as defined above.

In addition, the present invention encompasses compounds of Formula II: ##STR00017##
and the pharmaceutically acceptable salts thereof:
wherein

• n, k, m, R₃-R₆, X, T, W, and Z are defined as for Formula I;
• Q is phenyl or pyridyl substituted by up to 4 groups Y, where Y is independently selected at each occurrence from hydrogen, hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, nitro, amino, and mono- or dialkyl(C₁-C₆)amino. Compounds of Formula II, include compounds of Formula IIa, Formula IIb, Formula IIc, and Formula IId shown below ##STR00018##

The present invention also encompasses compounds of Formula III ##STR00019##
and the pharmaceutically acceptable salts thereof:
wherein

• n, k, m, R₃-R₆, X, T, W, and Z are defined as for Formula I;
• Q is phenyl or pyridyl substituted by up to 4 groups Y, where Y is independently selected at each occurrence from hydrogen, hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, nitro, amino, and mono- or dialkyl(C₁-C₆)amino. Particular compounds of Formula III include compounds of Formula IIIa and Formula IIIb shown below. ##STR00020##

The present invention also encompasses compounds of Formula IV ##STR00021##
and the pharmaceutically acceptable salts thereof:
wherein

• n, m, R₃-R₆, X, T, W, and Z are defined as for Formula I;
• Q is phenyl or pyridyl substituted by up to 4 groups Y, where Y is independently selected at each occurrence from hydrogen, hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, nitro, amino, and mono- or dialkyl(C₁-C₆)amino. Particularly included as compounds of Formula IV are compounds of Formula IV-1, Formula IV-2, and Formula IV-3, shown below. ##STR00022##

Preferred compounds of Formula IV, IV-1, IV-2, and IV-3 are those compounds where Z is a group —OR and R is hydrogen or alkyl wherein the alkyl is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy.

Other preferred compounds of Formula IV, IV-1, IV-2, and IV-3 are those compounds where Z is a group —NR_aR_b wherein

• R_a and R_b are independently hydrogen or alkyl wherein each alkyl is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; or
• R_a and R_b may be joined to form a heterocycloalkyl ring.

Further included as compounds of Formula IV are compounds of Formula IVa and IVb: ##STR00023##

The present invention also encompasses compounds of Formula V. ##STR00024##
wherein

• n, m, R₃-R₆, X, T, W, and Z are defined as for Formula I;
• Q is phenyl or pyridyl substituted by up to 4 groups Y, where Y is independently selected at each occurrence from hydrogen, hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, nitro, amino, and mono- or dialkyl(C₁-C₆)amino. Particularly included as compounds of Formula V are compounds of Formula Va, Formula Vb ##STR00025##

Especially preferred compounds of Formula V, Va, Vb, and Vc are compounds of wherein Z is a groups —NR_aR_b wherein R_a and R_b are independently hydrogen or alkyl wherein each alkyl is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; or R_a and R_b may be joined to form a heterocycloalkyl ring.

The present invention also encompasses compounds of Formula VI. ##STR00026##
and the pharmaceutically acceptable salts thereof:
wherein

• n, m, R₃-R₆, X, T, and Z are defined as for Formula I;
• Q is phenyl or pyridyl substituted by up to 4 groups Y, where Y is independently selected at each occurrence from hydrogen, hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, nitro, amino, and mono- or dialkyl(C₁-C₆)amino. Particularly included as compounds of Formula VI are compounds of Formula VIa and Formula VIb (shown below). ##STR00027##
  The present invention also encompasses compounds of Formula VII. ##STR00028##
  wherein W, Z, m, n, R₃, R₄, R₅, and R₆ are defined as for Formula I.

The present invention also encompasses compounds of Formula VIII. ##STR00029##
wherein W, Z, m, n, R₃, R₄, R₅, and R₆ are defined for Formula I.

The present invention also encompasses compounds of Formula IX. ##STR00030##
wherein W, Z, k, m, n, R₃, R₄, R₅, and R₆ are defined as for Formula I.

The present invention also encompasses compounds of Formula X. ##STR00031##
wherein W, Z, k, m, n, R₃, R₄, R₅, and R₆ are defined as for Formula I.

Preferred compounds of the invention are those where n is 1 or 2. Particularly preferred are those where X and T are both hydrogen. Thus, preferred compounds of the invention have formulas A1 or B1. ##STR00032##

Preferred compounds of Formulas A1 and B1 are those where R₃, R₄, R₅ and R₆ are independently hydrogen or alkyl. More preferably, R₃, R₄, R₅ and R₆ are independently hydrogen, methyl, or ethyl. Even more preferably, R₃, R₄, R₅ and R₆ are hydrogen or methyl, where not more than 2 of R₃-R₆ are methyl. Particularly preferred are compounds where R₃ and R₄ are C₁-C₃ alkyl, most preferably methyl, when R₅ and R₆ are hydrogen or where R₅ and R₆ are C₁-C₃ alkyl, most preferably methyl, when R₃ and R₄ are hydrogen. Other particularly preferred compounds are those where R₃ is methyl and R₄-R₆ are hydrogen or R₆ is methyl and R₃-R₅ are hydrogen.

Preferred G substituents of the invention include the following: ##STR00033##
where

• R_a represents hydrogen or alkyl where the alkyl is optionally halogenated; and
• e is an integer of 1-3.

More preferred G substituents of formula A include those where e is 1, 2, or 3, and R_a is hydrogen, methyl, ethyl, isopropyl, or cyclopropyl. Particularly preferred G substituents of formula A include those where e is 1, 2, or 3, and R_a is hydrogen or methyl.

Another preferred G substituent is the following formula: ##STR00034##
where

• R_a represents hydrogen or alkyl where the alkyl is optionally halogenated; and
• e is an integer of 1-3.

More preferred G substituents of formula B include those where e is 1, 2, or 3; and R_a is hydrogen, methyl or ethyl. Particularly preferred G substituents of formula B include those where e is 1 or 2, and R_a is hydrogen or methyl.

Another preferred G substituent is the following formula: ##STR00035##
where

• Hal represents a halogen, preferably fluoro, bromo, or chloro;
• R_a and R_b independently represent hydrogen, C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₃-C₇cycloalkylC₁-C₆alkyl where the cycloalkyl group may be substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, or mono- or diC₁-C₆ alkylamino; and
• e is an integer of 2-3.

Preferred compounds having formula C as the G group include those where Hal is fluoro and e is 2, 3, or 4.

More preferred G substituents of formula C include those where R_a is hydrogen, methyl or ethyl; and R_b is hydrogen. Particularly preferred G substituents of formula C include those where e is 2; R_a is hydrogen or methyl; and R_b is hydrogen.

Another preferred G substituent is the following formula: ##STR00036##
where

• Hal represents a halogen, preferably fluoro, bromo, or chloro;
• R_a and R_b independently represent hydrogen, C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₃-C₇cycloalkylC₁-C₆alkyl where the cycloalkyl group may be substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, or mono- or diC₁-C₆ alkylamino; and
• e is an integer of 2-3.

Preferred compounds having formula C-1 as the G group include those where Hal is fluoro and e is 2, 3, or 4.

Another preferred G substituent is the following formula: ##STR00037##
where

• R_a represents hydrogen, alkyl, or C_3-7 cycloalkyl, or a group of the formula: ##STR00038##
•  where
  • p is 1, 2, or 3;
  • D and D′ independently represent oxygen, NR_y or CHR_y, provided that only one of D and D′ may be NR_y, where each R_y is hydrogen or C₁-C₆ alkyl; and
  • R_z is hydrogen or C₁-C₆ alkyl; and
• R_b represents hydrogen, alkyl, or acyl;
• Y and Y′ independently represent hydrogen or halogen; and
• e is an integer of 1-3.

More preferred G substituents of formula D are those where Y is hydrogen or fluorine; and e is 1 or 2. Particularly preferred G substituents of formula D are those where Y is hydrogen or fluorine; e is 1 or 2; R_a is hydrogen, C_1-3 alkyl, or cyclopropyl, and R_b is hydrogen, methyl, or acyl. Other particularly preferred G substituents of formula D are those where Y is hydrogen and Y′ is fluorine. Still other particularly preferred G groups of Formula D are those where e is 1 or 2; R_a is hydrogen, C_1-3 alkyl, cyclopropyl or cyclopropylmethyl, and R_b is hydrogen, methyl, or acyl.

Another preferred G substituent is the following formula: ##STR00039##
where

• R_a represents hydrogen, alkyl, or C_3-7 cycloalkyl; and
• R_b represents hydrogen, alkyl, or acyl; or
• R_a and R_b independently represent hydrogen, C₁-C₆ alkyl, C_3-7cycloalkylC₁-C₆alkyl; and
• Y and Y′ independently represent hydrogen or halogen; and
• e is an integer of 1-3.

More preferred G substituents of formula D are those where Y is hydrogen or fluorine; and e is 1 or 2. Particularly preferred G substituents of formula D are those where Y is hydrogen or fluorine; e is 1 or 2; R_a is hydrogen, C_1-3 alkyl, or cyclopropyl, and R_b is hydrogen, methyl, or acyl. Other particularly preferred G substituents of formula D are those where Y is hydrogen and Y′ is fluorine. Still other particularly preferred G groups of Formula D are those where e is 1 or 2; R_a is hydrogen, C_1-3 alkyl, cyclopropyl or cyclopropylmethyl, and R_b is hydrogen, methyl, or acyl.

Another preferred G substituent is the following formula: ##STR00040##
where Z is oxygen, nitrogen, or methylene; and m is 1 or 2.

Particularly preferred G substituents of formula E are those where Z is oxygen, and m is 1 or 2. Other particularly preferred G substituents of formula E are those where Z is nitrogen, and m is 1 or 2.

Another preferred G substituent is the following formula: ##STR00041##
where Z is oxygen or nitrogen; and m is 1 or 2.

Particularly preferred G substituents of formula F are those where Z is nitrogen, and m is 1 or 2.

Another preferred G substituent is the following formula: ##STR00042##
where Z is oxygen, nitrogen, or methylene; and m is 1 or 2.

Particularly preferred G substituents of formula H are those where Z is nitrogen, and m is 1 or 2.

Another preferred G substituent is the following formula: ##STR00043##
where

• R_a represents hydrogen, alkyl, or C_3-7 cycloalkyl;
• R_b represents hydrogen, alkyl, or acyl;
• Y and Y′ independently represent hydrogen or halogen; and
• e is an integer of 1-3.

More preferred G substituents of formula J are those where Y and Y′ are independently hydrogen or fluorine; and e is 1 or 2. Particularly preferred G substituents of formula J are those where and Y′ are independently hydrogen or fluorine; e is 1 or 2; R_a is hydrogen, C_1-3 alkyl, or cyclopropyl, and R_b is hydrogen, methyl, or acyl.

Another preferred G substituent is the following formula: ##STR00044##
where

• R_a and R_b independently represent hydrogen, C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₃-C₇cycloalkylC₁-C₆alkyl where the cycloalkyl group may be substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, or mono- or diC₁-C₆ alkylamino; and
• e is an integer of 2-3.

Another preferred G substituent is represented by the following formula: ##STR00045##
where

• R_h is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, or trifluoromethyl;
• s is 0, 1, 2 or 3, and the sum of s and m is not less than 1;
• R_o is hydroxy, C₁-C₆alkoxy, amino, mono- or diC₁-C₆alkylamino where each alkyl is independently optionally substituted with amino, mono- or diC₁-C₆alkylamino, or
• R_o is a group of the formula ##STR00046##
  • p is 1, 2, or 3;
  • D and D′ independently represent oxygen, NR_y or CHR_y provided that only one of D and D′ may be NR_y where each R_y is hydrogen or C₁-C₆ alkyl; or and
    • R_z is hydrogen or C₁-C₆ alkyl.

Preferred M groups are those where R_h is hydrogen or halogen, most preferably fluoro, and R_o is a group of the formula: ##STR00047##
where

• R₁₄ is hydrogen or C₁-C₆alkyl;
• R₁₅ is hydrogen or C₁-C₆alkyl;
• R₁₆ is hydrogen, ethyl, or methyl;
• R₁₇ is C₁-C₆alkyl; and
• J is a C₁-C₄ alkylene group, preferably methylene, ethylene, or propylene.

Particularly preferred groups of Formula M include those where s is 1 and R_o is ethoxy, hydroxy, ethylamino, diethylamino, morpholinyl, piperazinyl, 4-methylpiperazinyl, ##STR00048##

Other preferred compounds of the invention are those of Formula N-1. ##STR00049##
wherein:

• n is 1 or 2;
• X is hydrogen, or alkyl;
• R₃, R₄, R₅, and R₆ are the same or different and are independently selected at each occurrence from hydrogen or alkyl; and
• G represents phenyl or pyridyl, each of which is substituted with a group ##STR00050##
•  and optionally with halogen, alkyl, alkoxy, hydroxy, amino, or mono- or dialkylamino;
  where
  • K and M independently represent a bond or C₁-C₆ alkylene;
  • W represents —O—, —NH—, —NR₇— where R₇ represents hydrogen or alkyl, or C₁-C₃ alkylene; and
  • Z is hydrogen, hydroxy, cycloalkyl(alkoxy), amino, mono- or di(alkyl₁)amino, or azacycloalkyl, —O(alkyl₁), —S(O)_0-2(alkyl₁), —C(═O) (alkyl₁), —OC(═O)(alkyl₁), —OC(═O)H, —C(═O)O(alkyl₁), —C(═O)OH, —C(═O)NH(alkyl₁), —C(═O)N(alkyl₁)₂, —C(═O)NH₂, —NHC(═O) (alkyl₁), —NHC(═O)H, —N(alkyl₁)C(═O)(alkyl₁), —NHS(O)_0-2(alkyl₁), —N(alkyl₁)S(O)_0-2(alkyl₁), —S(O)_0-2NH(alkyl₁), —S(O)_0-2(alkyl₁)N(alkyl₁),
    • wherein each alkyl₁ is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy, or
  • Z is —N(R_N)₂S(O)_0-2(R_S) where
    • each R_N is independently hydrogen or alkyl where the alkyl is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy, and
    • R_S is hydroxy, alkoxy, alkyl where the alkyl is optionally substituted with hydroxy, alkoxy, trifluoromethyl, halogen, amino, mono- or di-alkylamino, or
    • R_s is heteroaryl unsubstituted or substituted with alkyl, hydroxy, alkoxy, trifluoromethyl, halogen, amino, or mono- or dialkylamino;
  • Z is phenyl or phenylalkyl where the phenyl portion is optionally substituted with alkyl, hydroxy, alkoxy, trifluoromethyl, halogen, amino, or mono- or di-alkylamino, or
  • Z is 2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or 3-pyrrolyl, azeditinyl, norborn-2-yl, or adamantan-2-yl; each of which may be substituted on a tertiary carbon or a secondary nitrogen with C₁-C₆alkyl, or
  • Z represents a group of the formula: ##STR00051##
  •  where
    • p is 1, 2, or 3;
    • D and D′ independently represent oxygen, NR_y or CHR_y provided that only one of D and D′ may be NR_y where each R_y is hydrogen or alkyl; and
    • R_z is hydrogen or alkyl, or
  • Z represents a group of the formula: ##STR00052##
  •  where
    • p is 1, 2, or 3; and
    • q is 0, 1, or 2; or
  • Z represents a group of the formula: ##STR00053##
  •  where
    • s is 0, 1, 2 or 3, and the sum of s and m is not less than 1;
    • R_o is hydroxy, C₁-C₆alkoxy, amino, mono- or dialkylamino where each alkyl is independently optionally substituted with amino, mono- or dialkylamino, or
    • R_o is a group of the formula ##STR00054##
    •  where p, D, D′, and R_z are as defined above.

Preferred compounds of formula N-I include those where X is hydrogen. Other preferred compounds of formula N-I are those where X is C₁-C₆ alkyl, most preferably, methyl.

More preferred compounds of N-I are those where K is a bond and W is oxygen. In other more preferred compounds of formula N-I, K is a bond and W is a bond or methylene.

Still more preferred compounds of N-I are those where M is C₂ or C₃ alkylene. In other more preferred compounds of formula N-I, M is C₂ or C₃ alkylene. In these more preferred compounds of formula N-I, G is phenyl. Alternatively, G is pyridyl in more preferred compounds of formula N-I.

In preferred compounds of formula N-I,

• Z is amino, mono- or di(alkyl)amino, or azacycloalkyl, —O(alkyl), —S(O)_0-2(alkyl), —C(═O)(alkyl), —OC(═O)(alkyl), —OC(═O)H, —C(═O)O(alkyl), —C(═O)OH, —C(═O)NH(alkyl), —C(═O)N(C₁-C₆ alkyl₁)₂, —C(═O)NH₂, —NHC(═O)(alkyl), —NHC(═O)H, —N(alkyl)C(═O)(alkyl), —NHS(O)_0-2(alkyl), —N(alkyl)S(O)_0-2(alkyl), —S(O)_0-2NH(alkyl), —S(O)_0-2(alkyl)N(alkyl), or
• Z is —N(R_N)₂SO₂(R_S) where
  • each R_N is independently hydrogen or alkyl, and
  • R_S is hydroxy, alkoxy, or alkyl where the alkyl is optionally substituted with hydroxy, alkoxy, trifluoromethyl, halogen, amino, or mono- or di-alkylamino, or
  • R_S is phenyl, imidazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, each of which is optionally substituted with alkyl, hydroxy, alkoxy, trifluoromethyl, halogen, amino, or mono- or dialkylamino.

Preferred compounds of Formula I above (including all subformulae such as IIb, IIC etc), exhibit K_i values of less than 100 nM at the GABA_A receptor as determined by an assay of GABA_A receptor binding, especially preferred compounds of Formula I-X exhibit K_i values of less than 10 nM at the GABA_A receptor as determined by an assay of GABA_A receptor binding.

Representative compounds of the invention are shown below in Table 1.

TABLE 1

Compound 1   ##STR00055##
Compound 2   ##STR00056##
Compound 3   ##STR00057##
Compound 4   ##STR00058##
Compound 5   ##STR00059##
Compound 6   ##STR00060##
Compound 7   ##STR00061##
Compound 8   ##STR00062##
Compound 9   ##STR00063##
Compound 10  ##STR00064##
Compound 11  ##STR00065##
Compound 12  ##STR00066##
Compound 13  ##STR00067##
Compound 14  ##STR00068##
Compound 15  ##STR00069##
Compound 47  ##STR00070##
Compound 86  ##STR00071##
Compound 95  ##STR00072##
Compound 115 ##STR00073##
Compound 145 ##STR00074##
Compound 148 ##STR00075##
Compound 149 ##STR00076##
Compound 179 ##STR00077##
Compound 222 ##STR00078##
Compound 226 ##STR00079##
Compound 227 ##STR00080##
Compound 229 ##STR00081##
Compound 235 ##STR00082##

The following numbering conventions are used to identify positions on the ring systems in the compounds of the invention: ##STR00083##

Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable salts. Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)_n—COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table 1 and their pharmaceutically acceptable salts. The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.

This invention relates to fused pyrrolecarboxamide compounds that bind with high affinity to the benzodiazepine site of GABA_A receptors, including human GABA_A receptors. This invention also includes such compounds that bind with high selectivity to the benzodiazepine site of GABA_A receptors, including human GABA_A receptors. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of Formula I with the benzodiazepine site results in the pharmaceutical utility of these compounds.

The invention further comprises methods of treating patients in need of such treatment with an amount of a compound of the invention sufficient to alter the symptoms of a CNS disorder. Compounds of the inventions that act as agonists at α₂β₃γ₂ and α₃β₃γ₂ receptor subtypes are useful in treating anxiety disorders such as panic disorder, obsessive compulsive disorder and generalized anxiety disorder; stress disorders including post-traumatic stress, and acute stress disorders. Compounds of the inventions that act as agonists at α₂β₃γ₂ and α₃β₃γ₂ receptor subtypes are also useful in treating depressive or bipolar disorders and in treating sleep disorders. Compounds of the invention that act as inverse agonists at the α₅β₃γ₂ receptor subtype or α₁β₂γ₂ and α₅β₃γ₂ receptor subtypes are useful in treating cognitive disorders including those resulting from Down Syndrome, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, and stroke related dementia. Compounds of the invention that act as agonists at the α₁β₂γ₂ receptor subtype are useful in treating convulsive disorders such as epilepsy. Compounds that act as antagonists at the benzodiazepine site are useful in reversing the effect of benzodiazepine overdose and in treating drug and alcohol addiction.

The diseases and/or disorders that can also be treated using compounds and compositions according to the invention include:

Depression, e.g. depression, atypical depression, bipolar disorder, depressed phase of bipolar disorder.

Anxiety, e.g. general anxiety disorder (GAD), agoraphobia, panic disorder +/− agoraphobia, social phobia, specific phobia, Post traumatic stress disorder, obsessive compulsive disorder (OCD), dysthymia, adjustment disorders with disturbance of mood and anxiety, separation anxiety disorder, anticipatory anxiety acute stress disorder, adjustment disorders, cyclothymia.

Sleep disorders, e.g. sleep disorders including primary insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, including nightmare disorder, sleep terror disorder, sleep disorders secondary to depression and/or anxiety or other mental disorders, substance induced sleep disorder.

Cognition Impairment, e.g. cognition impairment, Alzheimer's disease, Parkinson's disease, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), stroke, traumatic brain injury, AIDS associated dementia, and dementia associated with depression, anxiety or psychosis.

Attention Deficit Disorders, e.g. Attention Deficit Disorder (ADD), Attention Deficit and Hyperactivity Disorder (ADHD).

The invention also provides pharmaceutical compositions comprising compounds of the invention, including packaged pharmaceutical compositions for treating disorders responsive to GABA_A receptor modulation, e.g., treatment of anxiety, depression, sleep disorders or cognitive impairment by GABA_A receptor modulation. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one GABA_A receptor modulator as described supra and instructions (e.g., labeling) indicating the contained GABA_A receptor ligand is to be used for treating a disorder responsive to GABA_A receptor modulation in the patient.

In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another CNS active compound. Such CNS active compounds include, but are not limited to the following: for anxiety, serotonin receptor (e.g. 5-HT_1A) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRF₁) antagonists; for sleep disorders, melatonin receptor agonists; and for neurodegenerative disorders, such as Alzheimer's dementia, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists. Particularly the invention provides a method of potentiating the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) by administering an effective amount of a GABA agonist compound of the invention in combination with an SSRI.

Combination administration can be carried out in a fashion analogous to that disclosed in Da-Rocha, et al., J. Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; or Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see, the discussion of the use of the GABA_A receptor ligand 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a]phthalzine in combination with nicotinic agonists, muscarinic agonists, and acetylcholinesterase inhibitors, in PCT International publications Nos. WO 99/47142, WO 99/47171, and WO 99/47131, respectively. Also see in this regard PCT International publication No. WO 99/37303 for its discussion of the use of a class of GABA_A receptor ligands, 1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.

The present invention also pertains to methods of inhibiting the binding of benzodiazepine compounds, such as Ro15-1788, to the GABA_A receptors which methods involve contacting a compound of the invention with cells expressing GABA_A receptors, wherein the compound is present at a concentration sufficient to inhibit benzodiazepine binding to GABA_A receptors in vitro. This method includes inhibiting the binding of benzodiazepine compounds to GABA_A receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to inhibit the binding of benzodiazepine compounds to GABA_A receptors in vitro. In one embodiment, such methods are useful in treating benzodiazepine drug overdose. The amount of a compound that would be sufficient to inhibit the binding of a benzodiazepine compound to the GABA_A receptor may be readily determined via an GABA_A receptor binding assay, such as the assay described in Example 8. The GABA_A receptors used to determine in vitro binding may be obtained from a variety of sources, for example from preparations of rat cortex or from cells expressing cloned human GABA_A receptors.

The present invention also pertains to methods for altering the signal-transducing activity, particulary the chloride ion conductanc of GABA_A receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound of the invention. This method includes altering the signal-transducing activity of GABA_A receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to alter the signal-transducing activity of GABA_A receptors in vitro. The amount of a compound that would be sufficient to alter the signal-transducing activity of GABA_A receptors may be determined via a GABA_A receptor signal transduction assay, such as the assay described in Example 9.

The GABA_A receptor ligands provided by this invention and labeled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the GABA_A receptor.

Labeled derivatives the GABA_A receptor ligands provided by this invention are also useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).

Definitions

If the compounds of the present invention have asymmetric centers, then this invention includes all of the optical isomers and mixtures thereof.

In addition, compounds with carbon-carbon double bonds may occur in cis, trans, Z- and E- forms, with all isomeric forms of the compounds being included in the present invention.

A dashed line ( - - - ) in a Formula indicates an optional bond. Thus the Formula ##STR00084##
represents either ##STR00085##

When any variable (e.g., C₁-C₆ alkyl, alkyl₁, R₃, R₄, R₅, R₆, X, T, G, W, Z, k, or m) occurs more than one time in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.

By “alkyl” or “lower alkyl” in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

By “alkoxy” or “lower alkoxy” in the present invention is meant straight or branched chain alkyl group having 1-6 carbon atoms, attached to the parent molecular moiety through an oxygen atom. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

The term “alkenyl” is intended to include either straight or branched hydrocarbon chains containing at least one carbon-carbon double bond which may occur in any stable point along the chain. Examples of alkenyl groups include ethenyl and propenyl.

The term “alkynyl” is intended to include either a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond which may occur in any stable point along the chain, such as ethynyl and propynyl.

By “diC₁-C₆alkylamino” is meant an amino group carrying two C₁-C₆alkyl groups that are the same or different.

By “benzoxazinyl” as used herein is meant a moiety of the formula: ##STR00086##

A benzoxazin-6-yl group is depicted.

By “halogen” in the present invention is meant fluorine, bromine, chlorine, and iodine.

By “2-hydroxyethoxy” is meant a group of the formula: —OCH₂CH₂OH.

The term “aryl” refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred examples of aryl groups include phenyl and naphthyl. The aryl groups of the invention are unsubstituted or may be substituted as provided herein. Examples of suitable substituents include hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, nitro, amino, mono- or dialkyl(C₁-C₆)amino, carboxamide, and N-mono- or N,N-disubstituted carboxamide.

The term “heteroaryl” refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings. Examples of heteroaryl groups include, for example, pyridine, furan, thiophene, 5,6,7,8-tetrahydroisoquinoline and pyrimidine. Preferred examples of heteroaryl groups include thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, thiadiazolyl, benzothiazolyl, imidazo[1,2-a]pyridinyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl. These heteroaryl groups can be unsubstituted or may be substituted as provided herein. Examples of suitable substituents include hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, nitro, amino, mono- or dialkyl(C₁-C₆)amino, carboxamide, and N-mono- or N,N-disubstituted carboxamide.

By a 2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or 3-pyrrolyl, or adamantane-2-yl group that is substituted on a tertiary carbon or a secondary nitrogen with C₁-C₆ alkyl is meant any such group in which a hydrogen atom is replaced with an appropriate alkyl group. By way of example, such groups include the following: ##STR00087##

By “heterocycloalkyl” is meant a non-aromatic ring system comprising one or two rings of 4-, 5-, 6-, or 7-atoms per ring wherein at least one ring contains at least one and up to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. Such heterocycloalkyl groups include, for example, tetrahydropyridyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperazinyl, and tetrahydrofuryl. The heterocycloalkyl group can be attached to the parent molecular moiety through the heteroatom or through a carbon atom. These groups may be substituted with from one to four groups independently selected from alkyl, alkoxy, halogen, hydroxy, amino and mono- or dialkylamino groups. Preferred substituents are hydroxy, methoxy, ethoxy, chloro, fluoro, bromo, methyl and ethyl. More preferred heterocycloalkyl groups are those that are independently substituted with two of hydroxy, methoxy, ethoxy, chloro, fluoro, bromo, methyl or ethyl. Particularly preferred heterocycloalkyl groups are those that are substituted with one of hydroxy, methoxy, ethoxy, chloro, fluoro, bromo, methyl or ethyl.

By “N-alkylpiperazyl” in the invention is meant radicals of the formula: ##STR00088##
where R is a straight or branched chain lower alkyl as defined above.

By “acyclic moiety having 3-7 carbon atoms” is meant a cytobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Each of these groups may be substituted with alkyl, alkoxy, hydroxy, halogen, amino or mono- or dialkylamino. Preferred substituents are alkyl and alkoxy. Particularly preferred are alkyl with methyl and ethyl being most preferred.

Non-toxic pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formic, citric, malic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. The present invention also encompasses prodrugs of the compounds of Formula I.

The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies, which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.

Pharmaceutical Compositions

Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable solvents that may be used to prepare solvates of the compounds of the invention, such as water, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide.

The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It will be convenient to formulate these animal feed and drinking water compositions so that the animal takes in an appropriate quantity of the composition along with its diet. It will also be convenient to present the composition as a premix for addition to the feed or drinking water.

Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of anxiety, depression, or cognitive impairment a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of sleep disorders a single dose that rapidly reaches effective concentrations is desirable.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

Preferred compounds of the invention will have desirable pharmacological properties. Such properties include, but are not limited to oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lifes. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred.

Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcová, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).

Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lifes of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).

Preparation of Compounds

A general illustration of the preparation of compounds of Formula I in the present invention is given in Scheme I. ##STR00089##
where:

Ar is ##STR00090##
where Q, W, k, m, n, Z, R₃, R₄, R₅, and R₆ are as defined above.

Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples.

In some cases protection of reactive functionalities may be necessary to achieve some of the above transformations. In general the need for such protecting groups will be apparent to those skilled in the art of organic synthesis as well as the conditions necessary to attach and remove such groups. Representative examples of the preparation of various protected aniline derivatives are shown in Schemes II (1), (2) and (3). ##STR00091##

Compounds of Formula I where G is a group of, for example, formulas C, C-1, D, D-1, K or M can be made using the above outlined methods and, e.g., additional ester and amide coupling reactions. It may also be necessary to protect the indole ring nitrogen during the preparation of the compounds of the invention.

For example, compounds where R₀ is a dialkylamino group can be prepared from a 2-(4-nitrophenoxy)ethan-1-ol made as described above and oxidation of the hydroxy group, and subsequent formation of an acid chloride or active ester. The active ester or acid chloride may then be coupled to an appropriate amine and the resulting nitrophenyl compound used as shown in the above schemes. ##STR00092## ##STR00093##

Those skilled in the art will recognize that in certain instances it will be necessary to utilize different solvents or reagents to achieve some of the above transformations. Unless otherwise specified all reagents and solvent are of standard commercial grade and are used without further purification.

The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present inventions, as demonstrated by the following examples. In some cases, protection of certain reactive functionalities may be necessary to achieve some of the above transformations. In general, such need for protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to those skilled in the art of organic synthesis.

EXAMPLES

Example 1

Preparation of Starting Materials and Intermediates

The starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods.

Representative examples of methods for preparing intermediates of the invention are set forth below.

1. 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid

##STR00094##

4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid is prepared according to the following procedure. Potassium hydroxide (345 g, 6.15 mol) is dissolved in methyl alcohol (1.2 L) then cooled in an ice water bath. A solution of cyclohexanedione (714 g, 6.15 mol) in methyl alcohol (1.2 L), dissolved using gentle heat, is added dropwise to the cold, stirred KOH solution over 2 h. A solution of ethyl bromopyruvate (1200 g, 6.15 mol) in methyl alcohol (1.5 L) is then added dropwise over 3 h. The reaction mixture is allowed to reach ambient temperature and stirred an additional 14.5 h. While cooling the reaction mixture via a water bath, a solution of sodium hydroxide (492 g, 12.4 mol) in water (984 mL) is added dropwise over 2.5 h. After stirring at ambient temperature for 15.5 h, the reaction mixture is cooled in an ice water bath, 500 g of ice added, and the resulting mixture is then acidified with concentrated hydrochloric acid (ca 1 L) to pH 1. The reaction mixture is concentrated in vacuo, 1 L of ice is added, and the precipitate filtered, washed with ice water (3×200 mL), and then dried in a vacuum oven at 75° C. to afford 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (560 g). m.p. 137-138° C.

2. 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate

##STR00095##

To a stirred mixture of 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (640 g, 3.55 mol), potassium carbonate (1.7 kg, 10.65 mol) and cesium carbonate (100 g, 0.32 mol) in N,N-dimethylformamide (9.0 L) is added iodoethane (1250 g, 8.01 mol). The mixture is heated at 60° C. for 2 h. After cooling to ambient temperature, the mixture is filtered, the solid is rinsed with ethyl acetate, and the filtrate concentrated in vacuo. Water (2 L) is added then extracted with ethyl acetate (2×2 L); the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (642 g). A mixture of this ester (640 g, 3.07 mol) and ammonium acetate (426 g, 5.53 mol) in N,N-dimethylformamide (320 mL) is heated to 100° C. for 2 h. The reaction mixture is concentrated in vacuo, ice water (2.5 L) is added, and extracted with dichloromethane (2×3 L); the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate (357 g). A mixture of this ester (170 g, 0.82 mol) in ethyl alcohol (250 mL) and a solution of sodium hydroxide (165 g, 4.1 mol) in water (1 L) is heated at reflux for 1 h, then cooled in an ice water bath. Concentrated hydrochloric acid (350 mL) is added dropwise, the precipitate collected by filtration, rinsed with ice water (3×), and dried in a vacuum oven at 75° C. to afford 125 g of 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate. m.p. 269-270 C.

3. 4-[N-trifluoroacetyl-(methylaminomethyl)aniline

##STR00096##

A solution of p-nitrobenzylbromide (5.40 g, 25 mmol) in acetonitrile (60 ml) is added dropwise to a stirred solution of aqueous methylamine (65 mL, 40 wt. %, 0.75 mol) in acetonitrile (50 mL) at 0°. After stirring an additional 15 minutes, the solution is poured into brine and extracted 2× with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-(methylaminomethyl)nitrobenzene (4.04 g).

A solution of trifluoroacetic anhydride (4.46 mL, 31.6 mmol) in dichloromethane (10 mL) is added dropwise to a stirred solution of 4-(methylaminomethyl)nitrobenzene (4.04 g, 24.3 mmol) and pyridine (2.16 mL, 26.7 mmol) in dichloromethane (25 mL) at 0°. After stirring an additional 30 minutes, the solution is poured into aqueous 3.6N hydrochloric acid and extracted with dichloromethane. The organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-[N-trifluoroacetyl-(methylaminomethyl)]nitrobenzene (6.55 g).

Crude 4-[N-trifluoroacetyl-(methylaminomethyl)]nitrobenzene (6.55 g) is dissolved in ethyl alcohol (75 mL), added to 10% Pd/C (655 mg) in a Parr bottle and shaken under Hydrogen (50 PSI) for 4 hours. The mixture is filtered through Celite and concentrated in vacuo to give 4-[N-trifluoroacetyl-(methylaminomethyl)aniline (5.75 g).

The 3-aminoalkylanilines are prepared in a similar fashion according to the procedure generally set forth in part (1) of Scheme II above.

4. 4-amino-(N-trifluoroacetyl-2-methylaminoethoxy)benzene

##STR00097##

A mixture of p-nitrophenol (1.39 g, 10 mmol), 2-chloroethoxytrimethylsilane (3.2 ml, 20 mmol), potassium carbonate (4.15 g, 30 mmol), cesium carbonate (163 mg, 0.5 mmol), and sodium iodide (149 mg, 1 mmol) in N,N-dimethylformamide (10 ml) is heated at 75° for 19.5 hours. After cooling to ambient temperature, the mixture is diluted with ethyl acetate and filtered. The filtrate is washed with saturated aqueous sodium bicarbonate, then washed 2× with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and purified on Silica gel (1:1 ethyl acetate/hexanes) to give 4-nitro-(2-Hydroxyethoxy)benzene (1.25 g).

4-Nitro-(2-Hydroxyethoxy)benzene (1.13 g, 6.2 mmol) in thionyl chloride (10 mL) is heated at reflux for 3 hours then concentrated in vacuo. After cooling the residue in an ice water bath, saturated aqueous sodium bicarbonate is added and the precipitate collected, rinsed with water, and dried to give 4-nitro-(2-chloroethoxy)benzene (909 mg).

A mixture of 4-nitro-(2-chloroethoxy)benzene (781 mg, 3.9 mmol) and aqueous methylamine (15 mL, 40 wt. %) in isopropyl alcohol (15 mL) is heated in a sealed tube at 100° for 4 hours. After cooling in an ice water bath, the mixture is poured into brine and extracted 2× with dichloromethane, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-nitro-(2-methylaminoethoxy)benzene (697 mg).

To a solution of 4-nitro-(2-methylaminoethoxy)benzene (766 mg, 3.9 mmol) and pyridine (0.35 mL, 4.29 mmol) in dichloromethane (5 mL) at 0° C. is added dropwise trifluoroacetic anhydride (0.72 mL, 5.08 mmol). After stirring at 0° C. for 3.5 hours, the mixture is poured into aqueous 1.2 N hydrochloric acid and extracted with dichloromethane. The organic layer is washed with saturated aqueous sodium bicarbonate then brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-nitro-(N-trifluoroacetyl-2-methylaminoethoxy)benzene (1.06 g). Treatment of this nitro compound with 10% Palladium on carbon in ethyl alcohol (18 mL) in a Parr bottle under Hydrogen (55 PSI) for 2.25 hours affords 4-amino-(N-trifluoroacetyl-2-methylaminoethoxy)benzene (709 mg).

Example 2

##STR00098##

To a stirred solution of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (100 mg, 0.6 mmol) and triethylamine (0.15 mL, 1.1 mmol) in N,N-dimethylformamide (5 mL) at 0° C. is added ethyl chloroformate (0.1 mL, 1.1 mmol). After stirring an additional 1 hour, 3-(N-trifluoroacetyl-(methylaminomethyl)aniline (0.3 g, 1.3 mmol) is added. The reaction mixture is stirred for 4 hours, then poured into saturated aqueous ammonium chloride and extracted 2× with ethyl acetate. The combined organic layers are washed sequentially with brine, aqueous 2N hydrochloric acid, then brine, dried over sodium sulfate, filtered, and concentrated in vacuo. To the residue is added 15% aqueous potassium bicarbonate (5 mL) and methyl alcohol (3 mL), then heated at reflux for 3 hours. After cooling, the reaction mixture is extracted with ethyl acetate, the organic layer dried over sodium sulfate, filtered, and concentrated in vacuo to give N-[3-(methylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (Compound 1) m.p. 130-132° C.

Example 3

The following compounds are prepared essentially according to the procedures described in Schemes I-IV and further illustrated in Examples 1-2:

• (a) N-[3-(Methylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 1); mp 130-132° C.
• (b) N-[4-(Hydroxyethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 16); mp 245-247° C.
• (c) N-[4-(Methoxyethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 2).
• (d) N-[-4-(3-Methylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 17); mp 233-236° C.
• (e) N-[4-(Methoxymethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 18); mp 164-165° C.
• (f) N-[4-(Aminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 6); mp >200° C. (d).
• (g) N-[4-(Methylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 19); mp 217-219° C.
• (h) N-[2-Fluoro-4-(methylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 3); mp 186-188° C.
• (i) N-{4-[N-acetyl-(methylaminomethyl)phenyl]}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 20); mp 204-206° C.
• (j) N-[4-(Ethylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 21); mp 194-195° C.
• (k) N-[4-(Isopropylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 22); mp 164-166° C.
• (l) N-[4-(Cyclopropylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 5); mp 171-173° C.
• (m) N-[4-(Dimethylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 23); mp 216-218° C.
• (n) N-[4-(2-Aminoethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-ndole-3-carboxamide (Compound 24); mp 85-90° C.
• (o) N-[4-(2-Methylaminoethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 4); mp 197-200° C.
• (p) N-[4-(Methoxymethyl)phenyl]-4-oxo-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 25).
• (q) N-[4-(Methylaminomethyl)phenyl-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 7); mp 173-175° C.
• (r) N-{4-[N-acetyl-(methylaminomethyl)phenyl]}-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 26); mp 159-161° C.
• (s) N-[4-(Methylaminomethyl)phenyl]-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 27); mp 217-219° C.
• (t) N-[4-(Hydroxymethyl)phenyl]-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 28); mp 260-262° C.
• (u) N-[4-(2-Hydroxyethoxy)phenyl]-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 9); mp 245-247° C.
• (v) N-[3-(Methylaminomethyl)phenyl]-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 29); mp 172-174° C.
• (w) N-[4-(2-Hydroxyethoxy)phenyl]-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 30); mp 268-270° C.
• (x) N-[3-(Hydroxymethyl)phenyl]-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 8); mp 233-235° C.
• (y) N-[4-(Hydroxymethyl)phenyl]-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 31); mp 245-247° C.
• (z) N-[4-(Methylaminomethyl)phenyl]-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 32); mp 230-232° C.
• (aa) N-(1,3-Benzodioxol-5-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 10); mp 248-249° C.
• (bb) N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 11); mp 254-256° C.
• (cc) N-(3,4-Dihydro-2H-1,4-benzoxazin-6-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 33); mp 216° C.
• (dd) N-(2,2-Dimethyl-1,3-benzodioxol-5-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 34).
• (ee) N-(2,3-Dihydro-1H-indol-5-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 35); mp 283-286° C.
• (ff) N-(2,3-Dihydro-1H-indol-6-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 13); mp 322-323° C.
• (gg) N-(1,3-Benzodioxol-5-yl)-4-oxo-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 36).
• (hh) N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-oxo-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 37); mp 241-243° C.
• (ii) N-(4H-1,3-Benzodioxin-7-yl)-4-oxo-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 38); mp 251-252° C.
• (jj) N-(1,3-Benzodioxol-5-yl)-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 39); mp 210-212° C.
• (kk) N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 12); mp 222-223° C.
• (ll) N-(2,2-Dimethyl-1,3-benzodioxol-5-yl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 40); mp 155-157° C.
• (mm) N-(1,3-Benzodioxol-5-yl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 41); mp 297-299° C.
• (nn) N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 42); mp 290-292° C.
• (oo) N-(1,3-Benzodioxol-5-yl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 43); mp 245-246° C.
• (pp) N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 44).
• (qq) N-(4H-1,3-Benzodioxin-7-yl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 45); mp 234-236° C.
• (rr) N-[(2-Hydroxyethoxy)pyrid-5-yl]-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 15); mp 221-223° C.
• (ss) N-(3,4-Dihydro-2H-1,4-benzoxazin-7-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 46).
• (tt) N-[4-(2-Pyrrolidinylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; [alternate name: (4-oxo(5,6,7-trihydroindol-3-yl))-N-[4-(2-pyrrolidinylethoxy)phenyl]carboxamide] (Compound 47);
• (uu) N-[3-(2-Dimethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide [alternate name: (4-oxo(5,6,7-trihydroindol-3-yl))-N-[4-(2-Dimethylaminoethoxy)phenyl]carboxamide] (Compound 48);
• (vv) N-[3-(2-n-Propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 49).
• (ww) N-[3-(2-n-Butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 50).
• (xx) N-[3-(2-Isobutylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 51) (syrup).
• (yy) N-[3-(2-Cyclobutylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 52).
• (zz) N-[3-(2-t-Butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 53).
• (aaa) N-[3-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 54).
• (bbb) N-{3-[2-(4-Methylcyclohexyl)aminoethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 55).
• (ccc) N-{3-[2-(3-Trifluoromethylbenzylamino)ethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 56).
• (ddd) N-{3-[3-(3-Trifluoromethylbenzylamino)propoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 57).
• (eee) N-[4-(2-Dimethylaminoethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 58).
• (fff) N-[4-(2-Pyrrolidin-1-ylethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 59); mp 184-186° C.
• (ggg) N-[4-(2-Diisopropylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 60).
• (hhh) N-[4-(2-Methylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 61).
• (iii) N-[4-(2-Ethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 62); mp 140-141° C.
• (jjj) N-[2-Fluoro-4-(2-ethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 63).
• (kkk) N-[4-(2-n-Propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 64); mp 130-133° C.
• (lll) N-[2-Fluoro-4-(2-n-propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 65).
• (mmm) N-[3-Fluoro-4-(2-n-propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 66).
• (mmm-a) N-[3-Fluoro-4-(2-n-propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride (Compound 67); mp 373° C.
• (nnn) N-[4-(2-Cyclopropylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 68).
• (ooo) N-[4-(2-Isopropylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 69); mp 284-286° C.
• (ppp) N-[4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 70).
• (ppp-a) N-[4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hemifumarate (Compound 71); mp 234-234° C.
• (qqq) N-[2-Fluoro-4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 72); mp 247-250° C.
• (rrr) N-[3-Fluoro-4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 73).
• (rrr-a) N-[3-Fluoro-4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide tosylate (Compound 74); mp 222° C.
• (sss) N-[4-(2-Isobutylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 75); dust.
• (ttt) N-[2-Fluoro-4-(2-Isobutylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 76); mp 152-155° C.
• (uuu) N-[3-Fluoro-4-(2-Isobutylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 77); mp 147-149° C.
• (vvv) N-[4-(2-n-Butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 78).
• (vvv-a) N-[4-(2-n-butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride (Compound 79); mp 187-190° C.
• (www) N-[3-Fluoro-4-(2-n-butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 80).
• (xxx) N-[4-(2-t-Butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 81); mp 290-292° C.
• (yyy) N-[3-Fluoro-4-(2-t-butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 82).
• (aaaa) N-[4-(2-adamant-2-ylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 83); mp 144-149° C.
• (bbbb) N-{4-[(R)-Pyrrolidin-2-ylmethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 84); mp 164-167-170° C.
• (cccc) N-{4-[(S)-Pyrrolidin-2-ylmethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 85); mp 165-167° C.
• (dddd) N-[4-(Piperidin-3-ylmethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 86).
• (dddd-a) N-[4-(Piperidin-3-ylmethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride (Compound 87); mp 196-199° C.
• (eeee) N-[4-(2-Dimethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 88); mp 201° C.
• (ffff) N-[3-Fluoro-4-(2-dimethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 89); mp 203° C.
• (gggg) N-[4-(2-Pyrrolidin-1-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 90); mp 164-168° C.
• (hhhh) N-[4-(2-Imidaz-1-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 91); mp 226-230° C.
• (iiii) N-[3-Fluoro-4-(2-moropholin-1-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 92); mp 200° C.
• (jjjj) N-[3-Fluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 93).
• (kkkk) N-[4-(2-Piperidin-2-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 94); mp 281-285° C.
• (llll) N-{4-[3-(2,2,2,-Trifluoroethyl)aminopropoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 95).
• (mmmm) N-[4-(3-Isopropylaminopropoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 96).
• (nnnn) N-{4-[3-(2-Methylpropyl)aminopropoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 97).
• (oooo) N-[4-(3-Isobutylaminopropoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 98).
• (pppp) N-[4-(3-Cyclopropylmethylaminopropoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 99).
• (qqqq) N-{4-[3-(3-Ethylpropyl)aminopropoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 100).
• (rrrr) N-[4-(3-Cyclopentylaminopropoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 101).
• (ssss) N-{4-[3-(N-Cyclopropylmethyl,N-propyl)aminopropoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 102).
• (tttt) N-[4-(2-Methylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 103).
• (uuuu) N-[4-(2-Ethylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 104).
• (uuuu-a) N-[4-(2-Ethylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride (Compound 105); mp 178-180° C.
• (vvvv) N-[4-(2-n-Propylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 106).
• (vvvv-a) N-[4-(2-n-Propylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride (Compound 107); mp 177-178° C.
• (wwww) N-[4-(2-Isopropylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 108).
• (wwww-a) N-[4-(2-Isopropylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride (Compound 109); mp 167-169° C.
• (xxxx) N-[4-(2-n-Butylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 110).
• (xxxx-a) N-[4-(2-n-Butylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride (Compound 111); mp 157-159° C.
• (yyyy) N-[4-(2-t-Butylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 112); mp 274-278° C.
• (zzzz) N-[4-(2-Benzylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 113)
• (zzzz-a) N-[4-(2-Benzylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride (Compound 114); mp 143-145° C.
• (aaaaa-a) N-[4-(Pyrid-3-ylmethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 115).
• (aaaaa) N-[4-(Pyrid-3-ylmethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride (Compound 116); mp 276-277° C.
• (bbbbb) N-[4-(Pyrid-4-ylmethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 117).
• (bbbbb-a) N-[4-(Pyrid-4-ylmethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride (Compound 118); mp 293° C.
• (ccccc) N-{4-[(R)-Pyrrolidn-2-ylmethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 119); mp 195-198° C.
• (ccccc-a) N-{4-[(R)-Pyrrolidn-2-ylmethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride (Compound 120); mp 289-291° C.
• (ddddd) N-{4-[(S)-Pyrrolidn-2-ylmethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 121); mp 138-141° C.
• (eeeee) N-[4-(2-Dimethylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 122); mp 163-166° C.
• (fffff) N-[4-(3-Dimethylaminopropoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 123); mp 247° C.
• (ggggg) N-[4-(2-Pyrrolidin-1-ylethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 124)
• (ggggg-a) N-[4-(2-Pyrrolidin-1-ylethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride (Compound 125); mp 188-245° C. (d).
• (hhhhh) N-[4-(2-Dimethylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 126).
• (iiiii) N-{4-[2-(4-Methyl-piperazin-1-yl)ethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 127).
• (jjjjj) N-{4-[2-Morpholin-1-ylethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 128).
• (kkkkk) N-{4-[2-Piperidin-1-ylethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 129).
• (kkkkk-a) N-{4-[2-Piperidin-1-ylethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride (Compound 130); mp 208-211° C.
• (lllll) N-{4-[(1-Methyl-pyrrolidin-3-yl)methoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 131); mp 209-211° C.
• (mmmmm) N-{4-[(1-Ethyl-pyrrolidin-3-yl)methoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 132).
• (nnnnn) N-{4-[2-(1-Methyl-pyrrolidin-2-yl)ethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 133).
• (ooooo) N-{4-[2-(1-Methyl-pyrrolidin-2-yl)ethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrate (Compound 134).
• (ppppp) N-[4-(3-n-Propylaminopropoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 135).
• (qqqqq) N-[4-(3-Cyclopropylmethylaminopropoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 136).
• (rrrrr) N-{4-[3-(2-Ethylbutyl)aminopropoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 137).
• (sssss) N-[4-(3-Cyclohexylaminopropoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 138).
• (ttttt) N-[4-(3-Cyclohexylmethylaminopropoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 139).
• (uuuuu) N-{4-[3-(Pyrid-4-ylmethyl)aminopropoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 140).
• (vvvvv) N-[4-(2-Pyrrolidin-1-ylethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 141); mp 148-150° C.
• (wwwww) N-[4-(3-Di-n-propylaminopropoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 142).
• (xxxxx) N-{4-[3-Di(c-propylmethyl)aminopropoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 143).
• (yyyyy) N-{4-[3-Di(2-ethylbutyl)aminopropoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 144).
• (zzzzz) N-{4-[3-Di(pyrid-4-ylmethyl)aminopropoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 145).
• (aaaaaa) N-{4-[2-(2-Pyrrolidin-1-ylethoxy)ethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 146).
• (bbbbbb) N-{4-[2-(2,2-Dimethylaminoethylamino)-2-oxoethyl]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 147).
• (cccccc) N-{4-[2-(4-Methylaminopiperizin-1yl)-2-oxoethyl]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 148); oil.
• (dddddd) N-{4-[7-azabicyclo(2.2.1)hept-2-yloxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 149).
• (eeeeee) N-[3-(2-Diethylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 150).
• (ffffff) N-[3-(2-Pyrrolidin-1-ylethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 151).
• (gggggg) N-[3-(2-Di-Isopropylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 152).
• (hhhhhh) N-[3-(2-n-Propylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 153).
• (iiiiii) N-[3-(2-n-Butylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 154).
• (jjjjjj) N-[3-(Methylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 155).
• (kkkkkk) N-{3-[3-(N-Ethyl,N-Methyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 156).
• (llllll) N-{3-[3-(N-Cyclopropylmethyl,N-n-propyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 157).
• (mmmmmm) N-[3-(Azeditinylpropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 158).
• (nnnnnn) N-[3-(3-Ethylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 159).
• (oooooo) N-{3-{3-(2,2,2-Trifluoroethyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 160).
• (pppppp) N-[3-(3-n-Propylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 161).
• (rrrrrr) N-[3-(3-Isopropylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 163).
• (ssssss) N-[3-(3-Cyclopropylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 164).
• (tttttt) N-[3-(3-Cyclopropylmethylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 165).
• (uuuuuu) N-[3-(3-Cyclobutylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 166).
• (vvvvvv) N-[3-(3-Cyclohexylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 167).
• (wwwwww) N-{3-[3-(3-Ethylpropyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 168).
• (xxxxxx) N-{3-[3-(2-Methylpropyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 169).
• (yyyyyy) N-[3-(3-Isobutylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 170).
• (zzzzzz) N-[3-(3-t-Butylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 171).
• (aaaaaaa) N-{3-[3-(2-Methylbutyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 172).
• (bbbbbbb) N-[3-(3-Isoamylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 173).
• (ccccccc) N-{3-[3-(4-Methylpentyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 174).
• (ddddddd) N-{3-[3-(1,1-Dimethylpropyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 175).
• (eeeeeee) N-{3-[3-(3,3,-Dimethylbutyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 176).
• (fffffff) N-{3-[3-(2,4-Dimethylpent-3-yl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 177).
• (ggggggg) N-{3-[3-(4-Methylcyclohexyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 178).
• (hhhhhhh) N-{3-[3-(4-t-Butylcyclohexyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 179).
• (iiiiiii) N-{3-[3-(2,6-Dimethylcyclohexyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 180).
• (jjjjjjj) N-{3-[3-(1-Phenylethyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 181).
• (kkkkkkk) N-[3-(3-Norborn-2-ylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 182).
• (lllllll) N-[3-(3-Adamant-1-ylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 183); mp 175-176° C.
• (mmmmmmm) N-[3-(3-Norborn-2-ylmethylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 184).
• (nnnnnnn) N-[3-(3-Adamant-2-ylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 185).
• (ooooooo) N-[4-(2-Ethylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 186).
• (ooooooo-a) N-[4-(2-Ethylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide hydrochloride (Compound 187); mp 227-228° C.
• (ppppppp) N-[2-Fluoro-4-(2-Ethylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 188).
• (qqqqqqq) N-[4-(2-n-Propylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 189).
• (rrrrrrr) N-[4-(2-Cyclopropylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 190).
• (sssssss) N-4-(2-n-Butylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 191).
• (ttttttt) N-[4-(3-Ethylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 192).
• (uuuuuuu) N-{4-[3-(1-Phenyl-1-methylethyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 193).
• (vvvvvvv) N-[4-(Pyrid-3-ylmethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 194); mp 241-243° C.
• (wwwwwww) N-[4-(Pyrid-4-ylmethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 195).
• (wwwwwww-a) N-[4-(Pyrid-4-ylmethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide hydrochloride (Compound 196); mp 235-240° C. (d).
• (xxxxxxx) N-[4-(2-Dimethylaminoethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 197).
• (yyyyyyy) N-[4-(2-Diethylaminoethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 198).
• (zzzzzzz) N-[4-(2-Pyrrolidin-1-ylethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 199).
• (zzzzzzz-a) N-[4-(2-Pyrrolidin-1-ylethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide hydrochloride (Compound 200); mp 160-162° C.
• (aaaaaaaa) N-[4-(2-Piperidin-1-ylethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 201).
• (bbbbbbbb) N-{4-[2-(1-Methyl-pyrrolidin-2-yl)ethoxy]pyrid-3-yl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 202).
• (cccccccc) N-{4-[(1-Ethyl-pyrrolidin-3-yl)methoxy]pyrid-3-yl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 203); oil.
• (dddddddd) N-[4-(2-Morpholin-1-ylethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 204).
• (eeeeeeee) N-[4-(2-Diethylaminoethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 205).
• (ffffffff) N-[4-(2-n-Propylaminoethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 206).
• (ffffffff-a) N-[4-(2-n-Propylaminoethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide hydrochloride (Compound 207); mp 210° C.
• (gggggggg) N-[4-(2-Isopropylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 208).
• (hhhhhhhh) N-[4-(3-Isopropylaminoproxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 209).
• (iiiiiiii) N-[4-(3-Cyclopropylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 210).
• (jjjjjjjj) N-[4-(3-Cyclobutylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 211).
• (kkkkkkkk) N-[4-(3-Cyclopropylmethylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 212).
• (llllllll) N-[4-(3-Isobutylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 213).
• (mmmmmmmm) N-{4-[3-(2,2-Dimethylpropyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 214).
• (nnnnnnnn) N-{4-[3-(3-Ethylpropyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 215).
• (oooooooo) N-{4-[3-(2-Methylbutyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 216).
• (pppppppp) N-{4-[3-(2-Methylpropyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 217).
• (qqqqqqqq) N-[4-(3-i-Pentylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 218).
• (rrrrrrrr) N-[4-(3-Cyclohexylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 219).
• (ssssssss) N-{4-[3-(N-Cyclopropylmethyl,N-n-propyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 220).
• (tttttttt) N-[4-(3-Indan-2-ylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 221).
• (uuuuuuuu) N-[3-Fluoro-4-(2-ethoxy-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 222); mp 192-196° C.
• (vvvvvvvv) N-[3-Fluoro-4-(2-hydroxy-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 223); mp 246-248° C.
• (wwwwwwww) N-[3-Fluoro-4-(2-ethylamino-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 224).
• (xxxxxxxx) N-[3-Fluoro-4-(2-diethylamino-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 225); mp 193-196° C.
• (yyyyyyyy) N-{3-Fluoro-4-[2-(4-methylpiperizin-1-yl)-2-oxoethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 226).
• (zzzzzzzz) N-ethyl-N-[2-(ethylamino)ethyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide (Compound 227).
• (aaaaaaaaa) N-[2-(dipropylamino)ethyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide (Compound 228); mp 148-150° C.
• (bbbbbbbbb) N-[2-(diethylamino)ethyl]-N-methyl-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide (Compound 229); mp 220-228° C.
• (ccccccccc) N-[2-(diethylamino)ethyl]-N-ethyl-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide (Compound 230); mp 165-167° C.
• (ddddddddd) N-[4-(2-morpholin-4-yl-2-oxoethoxy)phenyl](4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carboxamide (Compound 231).
• (eeeeeeeee) N-[3-fluoro-4-(2-morpholin-4-yl-2-oxoethoxy)phenyl](4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carboxamide (Compound 232); mp 110° C.
• (fffffffff) (4-oxo-(4,5,6,7-trihydroindol-3-yl))-N-[4-(2-oxo-2-piperazinylethoxy)phenyl]carboxamide (Compound 233)
• (ggggggggg) N-[3-(diethylamino)propyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide (Compound 234)
• (hhhhhhhhh) N-[3-(diethylamino)propyl]-2-{2-fluoro-4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide (Compound 235).
• (iiiiiiiii) N-[4-(diethylamino)-1-methylbutyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide (Compound 236).
• (jjjjjjjjj) N-[4-(diethylamino)-1-methylbutyl]-2-{2-fluoro-4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide (Compound 237).

Example 4

The compounds shown in Tables I and II were prepared using methods similar to those given in Schemes I-IV and further illustrated by Examples 1 and 2.

TABLE I
##STR00099##
Cmd #	Name	G	Spectral Data
238	N-{4-(2-(ethyl-methanesulfonyl-amino)-ethoxy]phenyl}-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide	##STR00100##	LRMS calcd 419 found [M + 1]
239	N-[4-(3-methanesulfonyl-propoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro- 1H-indole-3-carboxamide	##STR00101##	LRMS calcd 390 found [M + 1] 391
240	N-4-{4-(2-(ethanesulfonyl-ethyl-amino)ethoxy]-phenyl}-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide	##STR00102##	LRMS calcd 433 found [M + 1] 434
241	N-(4-{2-[ethyl-(propane-1-sulfonyl)amino]ethoxy}phenyl)-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide	##STR00103##	LRMS calcd 447 found [M + 1] 448
242	N-(4-{2-[ethyl-(thiophene-3-sulfonyl)amino]ethoxy}phenyl)-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide	##STR00104##	LRMS calcd 504 found [M + 1] 505
243	N-{6-[2-(ethyl-methanesulfonyl-amino)ethoxy]pyridin-3-yl}-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide	##STR00105##	LRMS calcd 420 found [M + 1] 421
244	N-[6-(1-benzyl-1H-imidazol-2-ylmethoxy)-pyridin-3-yl]-4-oxo- 4,5,6,7-tetrahydro-IH-indole-3-carboxamide	##STR00106##	LRMS calcd 441 found [M + 1] 442
245	N-[2-(2-aminoethoxy)pyridin-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H- indole-3-carboxamide	##STR00107##	LRMS calcd 314 found [M + 1] 315
246	N-[6-(2-ethanesulfonylamino-ethoxy)pyridin-3-yl]-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00108##	LRMS calcd 406 found [M + 1] 407
247	N-[6-(2-methanesulfonylamino-ethoxy)-pyridin-3-yl]-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00109##	LRMS calcd 392 found [M + 1]393
248	N-[4-(2-methanesulfonylamino-ethoxy)phenyl]-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00110##	LRMS calcd 391 found [M + 1] 392
249	N-4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid[2-(2- methanesulfonylamino-ethoxy)-pyridin-3-yl]-amide	##STR00111##	LRMS calcd 392 found [M + 1] 393
250	N-{2-[2-(thiophene-2-sulfonylamino)ethoxy]pyridin-3-yl}-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide	##STR00112##	LRMS calcd 460 found [M + 1] 461
251	N-{6-[(pyridin-2-ylmethyl)-amino]-pyridin-3-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00113##	LRMS calcd 361 found [M + 1] 362
252	N-{6-[(pyridin-3-ylmethyl)-amino]-pyridin-3-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00114##	LRMS calcd 361 found [M + 1] 362
253	N-(4-ethoxy-3-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3- carboxamide	##STR00115##	LRMS calcd 316 found [M + 1] 317
254	N-acid[3-(2-ethoxy-ethoxy)-phenyl]-4-Oxo-4,5,6,7-tetrahydro-1H- indole-3-carboxamide	##STR00116##	LRMS calcd 342 found [M + 1] 343
255	N-(4-[1,2,4]triazol-1-ylmethyl-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H- indole-3-carboxamide	##STR00117##	LRMS calcd 335 found [M + 1] 336
256	N-{4-[2-(methanesulfonyl-methyl-amino)-ethyl]-phenyl}-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide	##STR00118##	LRMS calcd 389 found [M + 1] 390
257	N-[4-(2-methanesulfonylamino-ethyl)-phenyl]-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00119##	LRMS calcd 375 found [M + 1] 378
258	N-(4-methanesulfonylmethyl-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H- indole-3-carboxamide	##STR00120##	LRMS calcd 346 found [M + 1] 347
259	N-[4-(4-hydroxymethyl-imidazol-1-yl)-phenyl]-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00121##	LRMS calcd 350 found [M + 1] 351
260	N-[4-(2-methanesulfonyl-ethyl)-phenyl]-4-oxo-4,5,6,7-tetrahydro- 1H-indole-3-carboxamide	##STR00122##	LRMS calcd 360 found [M + 1] 361
261	(2-{4-[(4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carbonyl)-amino]- phenyl}-ethyl)-carbamic acid tert-butyl ester	##STR00123##	LRMS calcd 397 found [M + 1] 398
262	N-[4-(2-imidazol-1-yl-ethyl)-phenyl]-4-oxo-4,5,6,7-tetrahydro-1H- indole-3-carboxylic acid amide	##STR00124##	LRMS calcd 348 found [M + 1] 349
263	N-{4-[2-(thiophene-2-sulfonylamino)-ethyl]-phenyl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00125##	LRMS calcd 443 found [M + 1] 444
264	N-[4-(2-ethanesulfonylamino-ethyl)-phenyl]-4-oxo-4,5,6,7-tetrahydro-1H- indole-3-carboxamide	##STR00126##	LRMS calcd 389 found [M + 1] 390
265	N-{4-(2-(propane-1-sulfonylamino)ethyl]phenyl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00127##	LRMS calcd 403 found [M + 1] 404
266	N-(5-ethoxy-pyridin-2-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3- carboxamide	##STR00128##	LRMS calcd 378 found [M + 1] 379
267	N-[4-(3-methanesulfonylamino-propoxy)-phenyl]-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00129##	LRMS calcd 405 found [M + 1] 406
268	N-[4-(3-amino-propoxy)-phenyl]-4-oxo-4,5,6,7-tetrahydro-1H- indole-3-carboxamide	##STR00130##	LRMS calcd 327 found [M + 1] 328
269	N-(5-propoxy-pyridin-2-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3- carboxamide	##STR00131##	LRMS calcd 299 found [M + 1] 300
270	N-(5-propoxy-pyridin-2-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3- carboxamide	##STR00132##	LRMS calcd 313 found [M + 1] 314
271	N-imidazo[1,2-a]pyridin-6-yl-4-Oxo-4,5,6,7-tetrahydro-1H-indole-3- carboxamide	##STR00133##	LRMS calcd 294 found [M + 1] 295
272	N-(6-(3-(4-pyridinyl)propoxy)-3-pyridinyl)-4,5,6,7-tetrahydro-4-oxo- 1H-indole-3-carboxamide	##STR00134##	electrospray mass spectrum: m/z 391 [M + 1]
273	N-(6-(3-(3-pyridinyl)propoxy)-3-pyridinyl)-4,5,6,7-tetrahydro-4-oxo- 1H-indole-3-carboxamide	##STR00135##	electrospray mass spectrum: m/z 391 [M + 1]
274	N-(6-(3-(2-pyridinyl)propoxy)-3-pyridinyl)-4,5,6,7-tetrahydro-4-oxo- 1H-indole-3-carboxamide	##STR00136##	electrospray mass spectrum: m/z 391 [M + 1]
275	N-(6-(2-(2-pyridinyl)ethoxy)-3-pyridinyl)-4,5,6,7-tetrahydro-4-oxo- 1H-indole-3-carboxamide	##STR00137##	electrospray mass spectrum: m/z 375 [M − 1]
276	N-[2-(ethylamino)pyrid-5-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3- carboxamide	##STR00138##	M.W. 298.348; MS (M + 1) 299
277	N-[2-(methylarnino)pyrid-5-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole- 3-carboxamide	##STR00139##	M.W. 284.321; MS (M + 1) 285.
278	N-{2-[2-(pyrrolidin-1-yl)ethylamino]pyrid-5-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00140##	M.W. 298.348; MS (M + 1) 299.
279	N-[2-(propylamino)pyrid-5-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole- 3-carboxamide	##STR00141##	M.W. 312.375; MS (M + 1) 313
280	N-{2-[(2-methoxyethyl)amino]pyrid-5-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00142##	M.W. 328.375; MS (M + 1) 329
281	N-[2-(butylamino)pyrid-5-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole- 3-carboxamide	##STR00143##	M.W. 326.402; MS (M + 1) 327.
282	N-(6-ethoxypyridazin-3-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3- carboxamide	##STR00144##	M.W. 300.321; MS (M + 1) 301
283	N-(6-methoxypyridazin-3-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3- carboxamide	##STR00145##	M.W. 286.294; MS (M + 1) 287.
284	N-[6-(propylamino)pyridazin-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H- indole-3-carboxamide	##STR00146##	M.W. 313.363; MS (M + 1) 314.
285	N-[2-ethoxy-6-(ethylamino)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H- indole-3-carboxamide	##STR00147##	M.W. 300.321; MS (M + 1) 301.
286	N-{2-[N-methyl(ethylamino)]pyrid-5-yl}-1-methyl-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide	##STR00148##	M.W. 286.294; MS (M + 1) 287.
287	N-{2-[(2-methylpropyl)amino]pyrid-5-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00149##	M.W. 326.402; MS (M + 1) 327
288	N-[2-(acetamido)pyrid-5-yl]-4-oxo-4,5,6,7-tetrahydro-1H- indole-3-carboxamide	##STR00150##	M.W. 312.332; MS (M + 1) 313.
289	N-[2-(N-ethylacetamido)pyrid-5-yl]-4-oxo-4,5,6,7-tetrahydro-1H- indole-3-carboxamide	##STR00151##	M.W. 340.386; MS (M + 1) 341
290	N-{2-[2-(morpholin-4-yl)ethylamino]pyrid-5-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide	##STR00152##	M.W. 383.450; MS (M + 1) 384
291	N-(2-{[2-(N-methylacetamido)ethyl]amino}pyrid-5-yl)-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide	##STR00153##	M.W. 369.428; MS (M + 1) 370.
292	N-(2-ethoxy-4-methylpyrid-5-yl)-4-oxo-4,5,6,7-tetrahydro-1H- indole-3-carboxamide	##STR00154##	M.W. 313.360; MS (M + 1) 314.
304	4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid{4-[2- (thiophene-2-sulfonylamino)-ethoxy]phenyl}-amide	##STR00155##
305	4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid(4-[1,2,4]- triazol-1-yl-phenyl)-amide	##STR00156##	LRMS calcd 321; found [M + 1] 322
306	4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid{4-[3- (1-methyl-1H-imidazole-4-sulfonylamino)-propoxy]-phenyl}amide	##STR00157##	LRMS calcd 471; found [M + 1] 472
307	4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid imidazo [1,2-a]pyridin-5-ylamide	##STR00158##	LRMS calcd 294; found [M + 1] 295
308	4-Oxo-3a,4,5,6,7,7a-hexahydro-1H-indole-3-carboxylic acid[6-(3- propyl-[1,2,4]thidazol-5-ylamino)-pyridin-2-yl]amide	##STR00159##	1H NMR (CD3OD) 0.75-0.95(m, 3H), 1.62- 1.81(m, 5H), 2.60-2.75(m, 5H), 6.07(d, 1H)8.6(s, 1H) LCMS found [M + H] 305.2

TABLE II
##STR00160##
Cmd.
#	Name	G	Spectral Data
293	N-[6-(2-pyridin-3-yl-ethylamino)-pyridin-2-yl]-4-oxo-3a,4,5,6,7,7a- hexahydro-1H-indole-3-carboxylic acidamide	##STR00161##	LCMS found (M + H) 299.3
294	N-[6-(3-imidazol-1-yl-propylamino)-pyridin-2-yl)-4-oxo-3a,4,5,6,7,7a- hexahydro-1H-indole-3-carboxamide	##STR00162##	LCMS found (M + H) 379.3
295	N-[6-(3-propyl[1,2,4]thiadiazol-5-ylamino)-pyridin-2-yl]-4-oxo- 3a,4,5,6,7,7a-hexahydro-1H-indole-3-carboxamide	##STR00163##	LCMS found (M + H) 305.2
296	N-(6-ethylaminopyridin-2-yl)-4-oxo-3a,4,5,6,7,7a-hexahydro-1H-indole-3- carboxylic acid	##STR00164##	LCMS found (M + H) 299.3
297	4-oxo-3a,4,5,6,7,7a-hexahydro-1H-indole-3-carboxylic acid{6-(2-ethyl- imidazol-1yl)ethoxy)-pyridin-3-yl}amide	##STR00165##	LCMS found (M + H) 394.4
298	4-oxo-3a,4,5,6,7,7a-hexahydro-1H-indole-3-carboxylic acid[6-(2-imidazol- 1-yl-ethoxy)-pyridin-3-yl)-amide	##STR00166##	LCMS found (M + H) 366.4

Example 5

Intermediate Compounds

The intermediate compounds shown in TABLE III are prepared using the methods given in Schemes III and IV.

TABLE III
Cmp #	Scheme	Name	Structure	Data
299	3	N-Ethyl-pyridine-2,6-diamine	##STR00167##	LCMS found (M + H) 125
300	3	N-(3-Imidazol-1-yl-propyl)-pyridine-2,6-diamine	##STR00168##	LCMS found (M + H) 218
301	3	N-(2-Pyridin-2-yl-ethyl)-pyridine-2,6-diamine	##STR00169##	LCMS found (M + H) 215
302	4	4-(2-Imidazol-1-yl-ethoxy)-phenylamine	##STR00170##	LCMS found (M + H) 204
303	4	4-[2-(2-Ethyl-imidazol-1-yl)-ethoxy]phenylamine	##STR00171##	LCMS found (M + H) 232

Example 5

Water solubility for various compounds within the invention was determined and compared with that for compounds outside the scope of the invention. The compounds evaluated are encompassed by Formula II:

TABLE IV
##STR00172##
Formula II
Water Solubility (ug/ml)	Rx	Ry	n	R
23	H	H	1	##STR00173##
203	H	H	1	##STR00174##
143	H	H	2	##STR00175##
15	H	H	1	##STR00176##
1.0	H	H	1	##STR00177##
0.58	H	H	1	##STR00178##
0.34	H	H	1	##STR00179##
0.26	CH3	CH3	1	##STR00180##

Example 6

Preparation of Radiolabeled Probe Compounds of the Invention

The compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from of at least one of carbon (preferably ¹⁴C), hydrogen (preferably ³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I). Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.

Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Tritium labeled probe compounds can also be prepared, when appropriate, by sodium borotritide reduction. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate.

Example 7

Receptor Autoradiography

Receptor autoradiography (receptor mapping) is carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds of the invention prepared as described in the preceding Example.

Example 8

Binding Assay

This assay is a standard assay for GABA_A binding affinity. The high affinity and high selectivity of compounds of this invention for the benzodiazepine site of the GABA_A receptor is confirmed using the binding assay described in Thomas and Tallman (J. Bio. Chem. 1981; 156:9838-9842, and J. Neurosci. 1983; 3:433-440).

Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) of Buffer A (0.05 M Tris HCl buffer, pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4° C.) at 20,000×g for 20 minutes. The supernatant is decanted, the pellet rehomogenized in the same volume of buffer, and centrifuged again at 20,000×g. The supernatant of this centrifugation step is decanted and the pellet stored at −20° C. overnight. The pellet is then thawed and resuspended in 25 volumes of Buffer A (original wt/vol), centrifuged at 20,000×g and the supernatant decanted. This wash step is repeated once. The pellet is finally resuspended in 50 volumes of Buffer A.

Incubations containing 100 μl of tissue homogenate, 100 μl of radioligand, (0.5 nM ³H-Ro15-1788 [³H-Flumazenil], specific activity 80 Ci/mmol), and test compound or control (see below), and are brought to a total volume of 500 μl with Buffer A. Incubations are carried for 30 min at 4° C. and then rapidly filtered through Whatman GFB filters to separate free and bound ligand. Filters are washed twice with fresh Buffer A and counted in a liquid scintillation counter. Nonspecific binding (control) is determined by displacement of ³H Ro15-1788 with 10 μM Diazepam (Research Biochemicals International, Natick, Mass.). Data were collected in triplicate, averaged, and percent inhibition of total specific binding (Total Specific Binding=Total−Nonspecific) was calculated for each compound.

A competition binding curve is obtained with up to 11 points spanning the compound concentration range from 10⁻¹²M to 10⁻⁵M obtained per curve by the method described above for determining percent inhibition. K_i values are calculated according the Cheng-Prussof equation. When tested in this assay preferred compounds of the invention exihibit K_i values of less than 1 uM, more preferred compounds of the invention have K_i values of less than 500 nM, still more preferred compounds of the invention have K_i values of less than 100 nM, and even more preferred compounds have K_i values of less than 10 nM.

Results for several compounds of this invention are listed in Table V.

TABLE V

Compound
Number Ki (nM)


1      90
2      29
3      49
4      0.24
5      9
6      9
7      30
8      27
9      1.3
10     37
11     7
12     5
13     24
14     3
15     12

Example 9

Electrophysiology

The following assay is used to determine if a compound of the invention act as an agonist, an antagonist, or an inverse agonist at the benzodiazepine site of the GABA_A receptor.

Assays are carried out as described in White and Gurley (NeuroReport 6: 1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory (Receptors and Channels 3: 1-5, 1995) with modifications. Electrophysiological recordings are carried out using the two electrode voltage-clamp technique at a membrane holding potential of −70 mV. Xenopus laevis oocytes are enzymatically isolated and injected with non-polyadenylated cRNA mixed in a ratio of 4:1:4 for α, β and γ subunits, respectively. Of the nine combinations of α, β and γ subunits described in the White et al. publications, preferred combinations are α₁β₂γ₂, α₂β₃γ₂, α₃β₃γ₂, and α₅β₃γ₂. Preferably all of the subunit cRNAs in each combination are human clones or all are rat clones. The sequence of each of these cloned subunits is available from GENBANK, e.g., human α₁, GENBANK accession no. X14766, human α₂, GENBANK accession no. A28100; human α₃, GENBANK accession no. A28102; human α₅, GENBANK accession no. A28104; human α₂, GENBANK accession no. M82919; human β₃, GENBANK accession no. Z20136; human β₂, GENBANK accession no. X15376; rat α₁, GENBANK accession no. L08490, rat α₂, GENBANK accession no. L08491; rat α₃, GENBANK accession no. L_08492; rat α₅, GENBANK accession no. L08494; rat β₂, GENBANK accession no. X15467; rat β₃, GENBANK accession no. X15468; and rat γ₂, GENBANK accession no. L08497. For each subunit combination, sufficient message for each constituent subunit is injected to provide current amplitudes of >10 nA when 1 μM GABA is applied.

Compounds are evaluated against a GABA concentration that evokes <10% of the maximal evokable GABA current (e.g. 1 μM-9 μM). Each oocyte is exposed to increasing concentrations of compound in order to evaluate a concentration/effect relationship. Compound efficacy is calculated as a percent-change in current amplitude: 100*((Ic/I)−1), where Ic is the GABA evoked current amplitude observed in the presence of test compound and I is the GABA evoked current amplitude observed in the absence of the test compound.

Specificity of a compound for the benzodiazepine site is determined following completion of a concentration/effect curve. After washing the oocyte sufficiently to remove previously applied compound, the oocyte is exposed to GABA+1 μM RO15-1788, followed by exposure to GABA+1 μM RO15-1788+ test compound. Percent change due to addition of compound is calculated as described above. Any percent change observed in the presence of RO15-1788 is subtracted from the percent changes in current amplitude observed in the absence of 1 μM RO15-1788. These net values are used for the calculation of average efficacy and EC₅₀ values by standard methods. To evaluate average efficacy and EC₅₀ values, the concentration/effect data are averaged across cells and fit to the logistic equation.

The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

Claims

1. A compound of the formula: ##STR00181##

wherein Y is independently selected at each occurrence from hydrogen, hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C₁-C₆) amino;

T is halogen, hydrogen, hydroxyl, amino, alkyl or alkoxy;

W is chosen from —O—, —NH—, —NR₇—, —S(O)_0-2—, —C(═O)—, —OC(═O)—, —C(═O)O—, —C(═O)NH—, —NHC(═O)—, —NR₇C(═O)—, —NHS(O)_0-2—, —NR₇S(O)_0-2—, —S(O)_0-2NH—, —S(O)_0-2R₇H—, and CR₇R₈ where R₇ and R₈ are the same or different and represent hydrogen, alkyl, or R₇-R₈ taken together represents a cyclic moiety having 3-7 carbon atoms;

Z is hydroxy, cycloalkyl (alkoxy), amino, mono- or di (alkyl₁)amino, azacycloalkyl, —O(alkyl₁), —S(O)_0-2(alkyl₁), —OC(═O) (alkyl₁), —OC(═O)H, —C(═O)O(alkyl₁), —C(═O)OH, —C(═O)NH(alkyl₁), —C(═O)NH₂, —NHC(═O) (alkyl₁), —NHC(═O)H, —N(alkyl₁)C(═O) (alkyl₁), —NHS(O)_0-2(alkyl₁), —N(alkyl₁)S(O)_0-2(alkyl₁), —S(O)_0-2NH(alkyl₁), or —S(O)_0-2(alkyl₁)N(alkyl₁), wherein alkyl₁ is independently chosen at each occurrence and is straight, branched, or cyclic, may contain one or two double or triple bonds, and is unsubstituted or substituted with one or more substitutents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy, or

Z is phenyl or phenylalkyl where the phenyl portion is optionally substituted with alkyl, hydroxy, alkoxy, trifluoromethyl, halogen, amino, or mono- or di-alkylamino, or

Z is NR₉COR₁₀ where R₉ and R₁₀ are the same or different and represent hydrogen or alkyl or cycloalkyl, or

Z is connected, optionally through W, to Q to from a 1-6 membered ring; or

Z represents a group of the formula: ##STR00182##

 p is 1, 2, or 3;

 q is 0, 1, or 2; and

 R_z is hydrogen or alkyl; or

Z is a group of the formula: ##STR00183##

where

s is 0, 1, 2 or 3, and the sum of s and m is not less than 1;

R_o is hydroxy, C₁-C₆ alkoxy, amino, mono- or di-alkylamino where each alkyl is independently optionally substituted with amino, mono- or dialkylamino, or

R_o is a group of the formula ##STR00184##

where p, D, D′, and R_z are as defined above; ##STR00185##

independently represent a carbon chain optionally substituted with hydrogen, halogen, oxo, cyano, nitro, amino, mono or dialkylamino, straight or branched chain alkyl, alkenyl, alkynyl, trifluoromethyl, trifluoromethoxy, or cycloalkyl; wherein

k is 0, 1, 2, or 3;

m is 0, 1, 2, or 3; and

R₃, R₄, R₅, and R₆ are the same or different and are independently selected at each occurrence from hydrogen, alkyl, —COR₁₁ or —CO₂R₁₁ where R₁₁ is alkyl or cycloalkyl having 3-7 carbon atoms; or —CONR₁₂R₁₃ where R₁₂ and R₁₃ are selected independently from hydrogen, alkyl, cycloalkyl having 3-7 carbon atoms, phenyl, 2-, 3-, or 4-pyridyl, or NR₁₂R₁₃ forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or

R₃-R₄ are taken together to form a cyclic moiety having 3-7 carbon atoms; or

R₅-R₆ are taken together to form a cyclic moiety having 3-7 carbon atoms;

where each alkyl group forming an R₃, R₄, R₅, or R₆ substituent or portion thereof may be substituted independently with hydroxy or mono- or dialkylamino where each alkyl is independently alkyl or cycloalkyl.

2. A compound according to claim 1, of the formula: ##STR00186##

3. A compound according to claim 1, of the formula: ##STR00187##

4. A compound of the formula: ##STR00188##

5. A compound according to claim 4, of the formula: ##STR00190##

6. A compound according to claim 4, of the formula: ##STR00191##

7. A compound according to claim 4, of the formula: ##STR00192##

8. A compound according to claim 4, of the formula: ##STR00193##

9. A compound of the formula: ##STR00194##

10. A compound according to claim 9, of the formula: ##STR00195##

11. A compound according to claim 9, of the formula: ##STR00196##

wherein:

R_a and R_b are independently hydrogen or alkyl wherein each alkyl is independently straight, branched, or cyclic, may contain one or two double or triple bonds, and is unsubstituted or substituted with one or more substitutents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; or

R_a and R_b are joined to form a heterocycloalkyl ring; and

Y is independently selected at each occurrence from hydrogen, hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, nitro, amino, and mono- or dialkyl(C₁-C₆)amino.

12. A compound of the formula: ##STR00197##

13. A compound according to claim 4, of the formula: ##STR00198##

14. A compound which is

N-[4-(2-Pyrrolidinylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; or

N-{3-[2-(3-Trifluoromethylbenzylamino)ethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

15. A compound which is

N-{3-[3-(3-Trifluoromethylbenzylamino)propoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-[4-(2-Pyrrolidin-1-ylethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-[2-Fluoro-4-(2-n-propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; or

N-[3-Fluoro-4-(2-n-propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

16. A compound according to claim 1 which is

N-[3-Fluoro-4-(2-n-propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride;

N-[3-Fluoro-4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; or

N-[3-Fluoro-4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide tosylate.

17. A compound which is

N-[3-Fluoro-4-(2-Isobutylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-[3-Fluoro-4-(2-n-butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-[3-Fluoro-4-(2-t-butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-[4-(2-adamant-2-ylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-{4-[(R)-Pyrrolidin-2-ylmethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-{4-[(S)-Pyrrolidin-2-ylmethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; or

N-[4-(Piperidin-3-ylmethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

18. A compound which is

N-[4-(Piperidin-3-ylmethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride;

N-[3-Fluoro-4-(2-dimethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-[4-(2-Pyrrolidin-1-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-[3-Fluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-[4-(2-Piperidin-2-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-{4-[3-(2,2,2,-Trifluorethyl)aminopropoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; or

N-{4-[2-(4-Methylaminopiperizin-1 yl)-2-oxo-ethyl]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

19. A compound according to claim 1, which is

N-[3-Fluoro-4-(2-hydroxy-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-[3-Fluoro-4-(2-ethylamino-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-[3-Fluoro-4-(2-diethylamino-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; or

N-{3-Fluoro-4-[2-(4-methylpiperizin-1-yl)-2-oxoethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

20. A compound which is

N-ethyl-N-[2-(ethylamino)ethyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide;

N-[2-(dipropylamino)ethyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide;

N-[2-(diethylamino)ethyl]-N-methyl-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide;

N-[2-(diethylamino)ethyl]-N-ethyl-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide;

N-[3-fluoro-4-(2-morpholin-4-yl-2-oxoethoxy)phenyl](4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carboxamide;

(4-oxo-(4,5,6,7-trihydroindol-3-yl))-N-[4-(2-oxo-2-piperazinylethoxy)phenyl]carboxamide;

N-[3-(diethylamino)propyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide;

N-[3-(diethylamino)propyl]-2-{2-fluoro-4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide; or

N-[4-(diethylamino)-1-methylbutyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide.

21. A compound of the formula: ##STR00200##

22. A compound of formula A: ##STR00207##

23. A compound according to claim 22, wherein R_h is hydrogen or halogen, and R_o is a group of the formula: ##STR00210##

where

R₁₄ is hydrogen or C₁-C₆ alkyl;

R₁₅ is hydrogen or C₁-C₆ alkyl;

R₁₆ is hydrogen, ethyl, or methyl;

R₁₇ is C₁-C₆ alkyl; and

J is a C₁-C₄ alkylene group.

24. A compound according to claim 22, wherein s is 1 and R_o is ethoxy, hydroxy, ethylamino, diethylamino, morpholinyl, piperazinyl, 4-methylpiperazinyl, ##STR00211##

25. A pharmaceutical composition comprising a compound according to claim 4 combined with at least one pharmaceutically acceptable carrier or excipient.

26. A method for the treatment of a disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABA_A receptor, said method comprising administering to a patient in need of such treatment an effective amount of a compound of claim 4.

27. A method according to claim 26 wherein the disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABA_A receptor is anxiety, depression, a sleep disorder, or cognitive impairment.

28. A method for localizing GABA_A receptors in a tissue sample comprising contacting with the sample a detectably-labeled compound of claim 4 under conditions that permit binding of the compound to GABA_A receptors, washing the sample to remove unbound compound, and detecting the bound compound.

29. A method of inhibiting the binding of a benzodiazepine compound to a GABA_A receptor, said method comprising contacting a compound of claim 4 with cells expressing such a receptor in the presence of the benzodiazepine, wherein the compound is present at a concentration sufficient to inhibit the binding a benzodiazepine compound to a GABA_A receptor in vitro.

30. A packaged pharmaceutical composition comprising the pharmaceutical composition of claim 4 in a container and instructions for using the composition to treat a patient suffering from a disorder responsive to agonism, inverse agonism or antagonism of the GABA_A receptor.

31. The packaged pharmaceutical composition of claim 30, wherein said patient is suffering from anxiety, depression, a sleep disorder, cognitive impairment, or Alzheimer's dementia.

32. A compound of the formula: ##STR00212##

wherein

Y is halogen;

m is 1, 2 or 3; and

Z is amino or mono or dialkylamino.

33. A compound according to claim 32 wherein Z is monoalkylamino, m is 2, and Y is fluorine.

34. A compound of the formula: ##STR00213##

wherein

Y is hydrogen, halogen or hydroxy;

m is 1, 2 or 3; and

Z is amino or mono or dialkylamino.

35. A compound according to claim 10 wherein n is 1.

36. A method for altering the signal-transducing activity of GABA_A receptors, said method comprising exposing cells expressing such receptors to a compound according to claim 4 at a concentration sufficient to inhibit RO15-1788 binding to cells expressing a cloned human GABA_A receptor in vitro.